Number 3 March 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Volume 1 - Number 1 May - September 1997

Volume 24 - Number 3 March 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It is made for and by: clinicians and researchers in cytogenetics, molecular biology, oncology, haematology, and pathology. One main scope of the Atlas is to conjugate the scientific information provided by cytogenetics/molecular genetics to the clinical setting (diagnostics, prognostics and therapeutic design), another is to provide an encyclopedic knowledge in cancer genetics. The Atlas deals with cancer research and genomics. It is at the crossroads of research, virtual medical university (university and post-university e-learning), and telemedicine. It contributes to "meta-medicine", this mediation, using information technology, between the increasing amount of knowledge and the individual, having to use the information. Towards a personalized medicine of cancer.

It presents structured review articles ("cards") on: 1- Genes, 2- Leukemias, 3- Solid tumors, 4- Cancer-prone diseases, and also 5- "Deep insights": more traditional review articles on the above subjects and on surrounding topics. It also present 6- Case reports in hematology and 7- Educational items in the various related topics for students in Medicine and in Sciences. The Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles.

See also: http://documents.irevues.inist.fr/bitstream/handle/2042/56067/Scope.pdf

Editorial correspondance

Jean-Loup Huret, MD, PhD, [email protected]

Editor, Editorial Board and Publisher See:http://documents.irevues.inist.fr/bitstream/handle/2042/48485/Editor-editorial-board-and-publisher.pdf

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008. The Atlas is hosted by INIST-CNRS (http://www.inist.fr) Staff: Vanessa Le Berre Philippe Dessen is the Database Directorof the on-line version (Gustave Roussy Institute – Villejuif – France).

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The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS. Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Editors-in-Chief Jesús María Hernández Rivas (Salamanca, Spain) Paola Dal Cin (Boston, Massachusetts) Jean-Loup Huret (Poitiers, France) Hematology Section Editor Ana E. Rodríguez, Teresa Gonzalez (Salamanca, Spain) Bone Tumors Section Editor Judith Bovee (Leiden, Netherlands) Head and Neck Tumors Section Editor Cécile Badoual (Paris, France) Urinary Tumors Section Editor Paola Dal Cin (Boston, Massachusetts) Pediatric Tumors Section Editor Frederic G. Barr (Bethesda, Maryland) Cancer Prone Diseases Section Editor Gaia Roversi (Milano, Italy) Cell Cycle Section Editor João Agostinho Machado-Neto (São Paulo, Brazil) DNA Repair Section Editor Godefridus Peters (Amsterdam, Netherlands) Epigenetics Section Editor Roberto Piergentili (Rome, Italy) Hematopoeisis Section Editor Olga Weinberg (Boston, Massachusetts) Hormones and Growth factors Section Editor Gajanan V. Sherbet (Newcastle upon Tyne, UK) Mitosis Section Editor Patrizia Lavia (Rome, Italy) Oxidative stress Section Editor Thierry Soussi (Stockholm, Sweden/Paris, France) WNT pathway Section Editor Alessandro Beghini (Milano, Italy) B-cell activation Section Editors Anette Gjörloff Wingren, Barnabas Nyesiga (Malmö, Sweden) Board Members Sreeparna Banerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Alessandro Beghini Department of Health Sciences, University of Milan, Italy; [email protected] Judith Bovée 2300 RC Leiden, The Netherlands; [email protected] Antonio Cuneo Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy; [email protected] Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected] IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212, 91223 François Desangles Bretigny-sur-Orge, France; [email protected] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, OX37BN, UK Enric Domingo [email protected] Ayse Elif Erson- Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Bensan Ad Geurts van Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB Nijmegen, Kessel The Netherlands; [email protected] Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Children's Cancer Research Oskar A. Haas Institute Vienna, Vienna, Austria. [email protected] Anne Hagemeijer Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; [email protected] Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA; Nyla Heerema [email protected] Sakari Knuutila Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; [email protected] Lidia Larizza Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; l.larizza@auxologico Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Roderick Mc Leod Germany; [email protected] Cristina Mecucci Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Fredrik Mertens [email protected] Konstantin Miller Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Felix Mitelman [email protected] Hossain Mossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; [email protected] Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Stefan Nagel Germany; [email protected] Florence Pedeutour Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; [email protected] Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Memphis, Tennessee 38105- Susana Raimondi 3678, USA; [email protected] Clelia Tiziana Department of Biology, University of Bari, Bari, Italy; [email protected] Storlazzi Sabine Strehl CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; [email protected] Nancy Uhrhammer Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; [email protected] Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected] Roberta Vanni Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Italy; [email protected]

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(3) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Volume 24, Number 3, March 2020 Table of contents

Gene Section

ALDH1A1 (Aldehyde Dehydrogenase 1 family member A1) 102 Sinem Tunçer, Rümeysa Çamlica, Idris Yilmaz OOEP (Oocyte expressed protein) 112 Luigi Cristiano EEF1D (eukaryotic translation elongation factor 1 delta) 117 Luigi Cristiano

Leukaemia Section t(6;11)(q13;q12) EEF1G/OOEP 136 Luigi Cristiano Fibroblastic Reticular Cell Tumor 140 Luis Miguel Juárez Salcedo, Diego Conde Royo, Samir Dalia t(1;19)(q22;p13.2) MEF2D/DAZAP1 142 Tatiana Gindina t(1;19)(q22;p13.2) MEF2D/HNRNPUL1 144 Tatiana Gindina Langerhans cell histiocytosis 146 Ding-Bao Chen Atlas of Genetics and Cytogenetics in Oncology and Haematology

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ALDH1A1 (Aldehyde Dehydrogenase 1 family member A1) Sinem Tunçer, Rümeysa Çamlica, Idris Yilmaz Vocational School of Health Services, Bilecik Seyh Edebali University, 11230, Bilecik, Turkey Biotechnology Application and Research Center, Bilecik Seyh Edebali University, 11230, Bilecik, Turkey; [email protected] (ST); Department of Molecular Biology and Genetics, Bilecik Seyh Edebali University, 11230, Bilecik, Turkey; [email protected]; [email protected] (RC, IY)

Published in Atlas Database: April 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/ALDH1A1ID53077ch9q21.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70676/04-2019-ALDH1A1ID53077ch9q21.pdf DOI: 10.4267/2042/70676 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology

including proliferation, differentiation, and Abstract apoptosis. Aldehyde dehydrogenase 1A1 (ALDH1A1) is a Keywords member of the ALDH gene superfamily. Aldehyde ALDH1A1, retinaldehyde, retinoic acid, retinol, dehydrogenases (ALDHs) are responsible for the cancer, stem cell, alcohol metabolism of aldehydes (exogenous and endogenous) through NAD(P)+-dependent oxidation to their corresponding carboxylic acids or CoA Identity esters. Different biological functions have been Other names: ALDC, ALDH-E1, ALDH1, attributed to the different ALDH family members. ALDH11, HEL-9, HEL-S-53e, HEL12, PUMB1, The cytosolic enzyme ALDH1A1 is involved in the RALDH1 catalysis of retinol (vitamin A) metabolite HGNC (Hugo): ALDH1A1 retinaldehyde to retinoic acid (RA). RA acts as a ligand for the nuclear receptors retinoic receptor Location: 9q21.13 (RAR) and the retinoid X receptor (RXR) and Local order therefore regulates the transcriptional activity of Starts at 72900662 and ends at 72953317 (according genes involved in multiple important processes to GRCh38) (Figure 1).

Figure 1. Genomic location of human ALDH1A1 (Chromosome 9 - NC_000009.12, GRCh38.p12 Primary Assembly)

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(3) 102 ALDH1A1 (Aldehyde Dehydrogenase 1 family member A1) Tunçer S et al.

Transcription DNA/RNA This gene has 7 transcripts (splice variants), 161 The ALDH gene superfamily is found in Archaea, orthologues and 18 paralogues depending on Eubacteria and Eukarya, indicating a vital role for Ensembl release 95-January 2019 (Table 2). this family throughout evolutionary history (Jackson ENST00000297785.7 (ALDH1A1-201) transcript et al., 2011). has 13 exons, ENST00000376939.5 (ALDH1A1- A standardized gene nomenclature system based on 202) and ENST00000419959.5 (ALDH1A1-203) divergent evolution and amino acid identity was transcripts have 8 exons, and ENST00000446946.1 established for the ALDH superfamily in The Ninth (ALDH1A1-204) transcript has 7 exons (Figure 3). International Symposium on Enzymology and Molecular Biology of Carbonyl Metabolism, in 1998 Gene Species Gene Symbol Identity (%) DNA (Figure 2) (Marchitti et al., 2008). H.sapiens ALDH1A1 There are 19 known functional aldehyde vs. P.troglodytes ALDH1A1 99,5 dehydrogenase (ALDH) genes and many pseudogenes in the human genome (Tomita et al., vs. M.mulatta ALDH1A1 97,9 2016). ALDH1 family has six members including vs. C.lupus ALDH1A1 88,4 ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, vs. B.taurus ALDH1A1 90,2 ALDH1L1, and ALDH1L2 (C. K. Yang et al., 2017). vs. M.musculus Aldh1a1 84,6 Since vertebrate ALDH1A1, ALDH1A2 and vs. R.norvegicus Aldh1a1 83,9 ALDH1A3 subunit sequences are highly conserved: subsequent gene duplication events are thought to vs. G.gallus ALDH1A1 79,4 generate ALDH1A1, ALDH1A2 and ALDH1A3 vs. X.tropicalis aldh1a1 74,4 genes in most vertebrate genomes, except some bony vs. E.gossypii AGOS_ADR417W 54,1 fish (Holmes, 2015). ALDH1A1 homologs are vs. A.thaliana ALDH2C4 57,6 present in most vertebrae species, but are absent in vs. O.sativa Os01g0591000 56 Zebra fish and other fishes in the teleost lineage vs. O.sativa Os01g0591300 55,5 (Table 1) (Jackson et al., 2011). Table 1. Pairwise alignment of ALDH1A1 gene (in distance Description from human) (HomoloGene, NCBI).

The ALDH1A1 gene is a protein coding gene. The gene covers 52656 bp, from 72900662 to 72953317 (NC_000009.12). It is located on the plus strand spanning 13 exons (GRCh38, NCBI Homo sapiens Annotation Release 109). Figure 2. ALDH Nomenclature

Figure 3. Display of human ALDH1A1 gene transcript exons (Ensembl release 95 - January 2019)

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Name Transcript ID bp CCDS RefSeq dehydrogenase 1 (RALDH1), is an heterotetramer ALDH1A ENST000002977 210 CCDS66 NM_0006 enzyme that is encoded by the human ALDH1A1 1-201 85.7 7 44 89 gene. ALDH1A ENST000003769 Human ALDH1A1 is 501 amino acids in length 822 - - 1-202 39.5 (Table 3). ALDH1A1 protein similarity across ALDH1A ENST000004199 species are given in Table 4. 806 - - 1-203 59.5 Description ALDH1A ENST000004469 805 - - The human ALDH1 family shares over 60% protein 1-204 46.1 sequence identity and has six subfamily members (C. ALDH1A ENST000004822 879 - - K. Yang et al., 2017). 1-205 10.5 Crystal structures of mammalian ALDH enzymes ALDH1A ENST000004931 604 - - have shown that each subunit contains three 1-206 13.1 domains: (1) an NAD(P) + cofactorbinding domain, ALDH1A ENST000004933 209 - - (2) a catalytic domain, and (3) a bridging domain. A 1-207 11.1 funnel passage leading to the catalytic pocket is Table 2. Transcripts of human ALDH1A1 gene (Ensembl release 95-January 2019) found at the interface of these domains. Studies in human K562 erythroleukemia and Hep3B ALDH specificity toward particular aldehyde hepatoma cells showed that the ALDH1A1 promoter substrates is thought to be caused by the upper contains a positive regulatory region (-91 to +53 bp portion of the funnel which is composed of residues to the transcription start site) with a CCAAT box as from all three domains. a major cisacting element (Alam et al., 2013). The lower portion of the funnel appears to be the Among CCAAT-recognizing transcription factors, catalytic site where hydride transfer from substrate nuclear factor YA (NFYA) was shown to be to cofactor occur, is composed of highly conserved involved in ALDH1A1 transcription. Mamat et al. residues (Marchitti et al., 2008) (Figure 6). found that in cooperation with POU2F1 (Oct-1), Gene Species Gene Symbol Identity (%) Protein alternatively spliced isoforms of NFYA plays an important role in ALDH1A1 expression in H.sapiens ALDH1A1 endometrial adenocarcinoma (Mamat et al., 2011). vs. P.troglodytes ALDH1A1 100 In mouse hepatoma cells, RARA transactivates the vs. M.mulatta ALDH1A1 98,8 Aldh1a1 promoter by binding to the RARE region, vs. C.lupus ALDH1A1 89 located between -91 and -75 bp. Moreover, CEBPB vs. B.taurus ALDH1A1 91,2 has been demonstrated to transactivate the ALDH1A1 promoter by interacting with the vs. M.musculus Aldh1a1 87 CCAAT box that resides at -75 to -71 bp adjacent to vs. R.norvegicus Aldh1a1 86,4 the RARE (Alam et al., 2013). vs. G.gallus ALDH1A1 84,2 Pseudogene vs. X.tropicalis aldh1a1 78,2 Not identified. vs. E.gossypii AGOS_ADR417W 50,7 vs. A.thaliana ALDH2C4 52 Protein vs. O.sativa Os01g0591000 53,8 Aldehyde dehydrogenase 1 family, member A1, also vs. O.sativa Os01g0591300 51,8 known as ALDH1A1 or retinaldehyde Table 4. Pairwise alignment of ALDH1A1 protein sequences (in distance from human) (HomoloGene, NCBI)

Isoelectric Molecular Name Transcript ID bp Protein Charge CCDS UniProt RefSeq Point Weight ALDH1A1- 54,861.84 P00352 ENST00000297785.7 2107 501aa 1,0 6,6811 CCDS6644 NM_000689 NP_000680 201 g/mol V9HW83 ALDH1A1- 25,314.22 ENST00000376939.5 822 230aa -0,5 6,2427 - Q5SYQ9 - 202 g/mol ALDH1A1- 26,097.05 ENST00000419959.5 806 238aa -1,0 6.1061 - Q5SYQ8 - 203 g/mol ALDH1A1- 22,654.11 ENST00000446946.1 805 203aa -1,0 5,8174 - Q5SYQ7 - 204 g/mol

Table 3. Protein products of human ALDH1A1 gene (Ensembl release 95-January 2019)

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Expression ALDH8A1 (Tomita et al., 2016). The RA enters the cell nucleus and binds and activates RA receptors ALDH1A1 is a highly conserved homotetramer (RARs) or retinoid X receptors (RXRs) to regulate somatic cell plasma protein, expressed in numerous gene expression (Zhao et al., 2014). tissues, including liver, kidney, red blood cells, ALDH1A1 also plays a role in acetaldehyde skeletal muscle, lung, breast, lens, stomach, brain, metabolism. Acetaldehyde is the first product of pancreas, testis, prostate, ovary (Jackson et al., 2011; ethanol metabolism. Alcohol, taken with alcohol Mamat et al., 2011). The detailed RNA and protein consumption, is converted to acetaldehyde by expression information can be found in: Human alcohol dehydrogenase (ADH), catalase and Protein Atlas cytochrome P450 2E1. Then, acetaldehyde is (https://www.proteinatlas.org/ENSG00000165092- metabolized to acetates by ALDH2 and ALDH1A1. ALDH1A1/tissue). Indeed, low ALDH1A1 activity is suggested to be Localisation related to alcohol sensitivity in some Caucasian ALDH1A1 is present in the cytosol. Interestingly, populations ("Identification And Characterisation Of Kahlert et al. observed nuclear expression of Alcohol-Induced Flushing In Caucasian Subjects", ALDH1A1 in a small subgroup of patients with 2017). Moreover, decreased levels of ALDH1A1 colon cancer and rectal cancer, and found that in were shown in RXRA-/- mice, which were more colon cancer patients, nuclear expression of susceptible to alcoholic liver injury (Gyamfi, 2006), ALDH1A1 was significantly associated with while increased ALDH1A1 expression found in shortened overall survival (Kahlert et al., 2012). brains of alcohol-avoiding DBA/2 mice (Bhave et al., 2006). Function ALDH1A1 is predominantly expressed by a In retinol metabolism (Figure 4), retinol is oxidized subgroup of dopaminergic (DA) neurons in the by retinol dehydrogenases (RD) to retinal. Later on, midbrain (Maring et al., 1985). In DA neurons, retinal is oxidized to retinoic acid (RA) in a reaction ALDH1A1 mediates the oxidation of the cytotoxic catalyzed by the human ALDH isoenzymes dopamine intermediate, 3,4- ALDH1A1, ALDH1A2, ALDH1A3, and dihydroxyphenylacetaldehyde (DOPAL), to the less ALDH8A1The metabolized product RA includes reactive 3,4-dihydroxyphenylacetic acid (DOPAC), all-trans RA (ATRA), 9-cis RA, and 13-cis RA. The and thereby protects the DA neurons from toxicity ALDH isoforms, especially ALDH1A1, have an (Pan et al., 2019). Very recently, ALDH1A1 was affinity for ATRA and 9-cis RA. RA diffuses into reported to mediate the synthesis of the inhibitory the nucleus and acts as a ligand for the retinoic acid neurotransmitter gamma-aminobutyric acid receptors (RARA, RARB, RARG) and retinoic X (GABA) (Kim et al., 2015) in DA neurons, where receptors ( RXRA, RXRB, RXRG). Then, the co-release of dopamine and GABA regulates alcohol ligand-receptor complex binds to the retinoic acid consumption and preference (Pan et al., 2019). In response element (RARE) in the promoter of target addition, as a metabolic product of ALDH1A1, RA genes and therefore regulates differentiation, is known to play a crucial role in neuronal patterning, apoptosis and/or cell cycle arrest in a context- differentiation, and survival (Pan et al., 2019). dependent manner (Marcato et al., 2011b; Tomita et In addition to its role in aldehyde metabolism, al., 2016). RXRA-/- mice were shown to have ALDH1A1 possesses esterase activity. Collard et al. decreased liver ALDH1A1 levels, suggesting that proposed ALDH1A1 being the major if not the only RA binding is an activating factor in ALDH1A1 enzyme responsible for the oxidation of 3- gene expression (Gyamfi, 2006). RA is required for deoxyglucosone to 2-keto-3-deoxygluconate testicular development and ALDH1A1 is absent in (Collard et al., 2007). genital tissues of humans with androgen receptor- ALDHs are generally categorized as detoxification negative testicular feminization. Being an androgen enzymes. ALDH1A1 was found to offer cellular binding protein, ALDH1A1 expression is thought to protection against cytotoxic drugs and implicated in be regulated also by the androgen receptor (Li et al., drug-resistance in chemotherapy (Tomita et al., 2010; Marchitti et al., 2008). 2016). ALDH1A1 activity has been reported to Aldehyde dehydrogenase (ALDH) enzyme family provide cellular protection against some plays an important role in cellular signal oxazaphosphorine anticancer drugs, such as transmission and protection by catalyzing the cyclophosphamide (CP) and ifosfamide, by oxidation of aldehydes (Alam et al., 2013). detoxifying their major active aldehyde metabolites ALDH1A1 mainly contributes to the biosynthesis of (Hilton, 1984; Wang et al., 2017). retinoic acid (RA) from vitamin A (Van Der Waals ALDH1A1 also plays a vital role as a marker of stem et al., 2018). Inside the cell, Retinol (vitamin A) is cells and cancer stem cells. Experimental data oxidized to retinal by retinal dehydrogenases. The indicate that ALDH1 activity, predominantly retinal is then oxidized to RA in a reaction catalyzed attributed to isotype ALDH1A1, is tissue and cancer with ALDH1A1, ALDH1A2, ALDH1A3, and type specific. On the other hand, although elevated

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ALDH1 activity and ALDH1A1 overexpression are demonstrated that ALDH1A1 plays a crucial role in associated with poor cancer prognosis, high ALDH1 protecting the mouse eye lens and cornea by and ALDH1A1 levels are not always correlated with detoxifying lipid peroxidation-derived aldehydes highly malignant phenotypes and poor clinical and preventing cataract formation induced by outcome in a range of cancers (Tomita et al., 2016). oxidative stresses (Mice et al., 2008). It is suggested that ALDH1A1 can be a useful In addition to its catalytic functions, ALDH1A1 has marker for cancer stem cells derived from tumors also non-catalytic roles. that normally do not express high levels of Similar with other ALDHs, ALDH1A1 acts as ALDH1A1, including breast, lung, esophagus, corneal and lens crystallins in mammalian eye tissue colon, and stomach (Tomita et al., 2016; Xing et al., and contributes to the transparent and refractive 2014). properties of the eye (Vasiliou et al., 2013), as well ALDH1A1 also plays a key role in the cellular as protects the eye from tissue damage as mentioned defense against oxidative stress: ALDH activity is earlier. required to maintain sufficiently low Reactive Finally, since ALDH1A1 can bind thyroid hormone Oxygen Species (ROS) level. Human ALDH1A1 and its expression is induced by estrogens, it is was shown to efficiently oxidize lipid peroxidation- suggested that the enzyme may be regulated by or derived aldehydes, like 4-Hydroxynonenal (4-HNE), involved in hormone signaling (Marchitti et al., hexanal, and Malondialdehyde (MDA) (MANZER 2008). et al., 2003), and Aldh1a1 knock-out mouse models

Figure 4. Retinoic acid signaling pathway: Retinoic acid (RA), generated by ALDHs, can function in the paracrine or endocrine manner by diffusing into neighbouring cells or the nucleus. In the nucleus, RA binds to heterodimers of the retinoic acid receptor (RAR) and retinoid x receptor (RXR). Activated receptor complexes induce transcription of target genes by binding to retinoic acid response elements (RAREs).

Figure 5. ALDH1A1 regulation and function: Once inside the cytoplasm, retinol is oxidized to retinal, then retinal is oxidized to RA by several isoforms of ALDH. RA binds to dimers of RARA and RXRs to induce the expression of its downstream target genes. RA can bind to dimers of RXRs and ESR1 (ERα) as well as induce the expression of MYC and CCND1 (cyclin D1) in ERα-expressing cells. In addition to RA binding to the RAR, CEBPB and OCT1 binding to the ALDH1A1 promoter enhances the ALDH1A1 transcription. NFYA was also shown to activate ALDH1A1 transcription while DDB2 was shown to suppress ALDH1A1 expression by preventing CEBPB binding to the promoter. The details can be found in the text. The figure is modified from Tomita et al. (Tomita et al., 2016)).

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in an obese mouse model. Therefore, both in vivo and in vitro results suggest that retinaldehyde may act as an adipogenesis inhibiting signaling metabolite (Ziouzenkova et al., 2007). As an ALDH1A1 metabolite, RA has also an effect on adipogenesis. RA treatment of obese mice resulted in weight loss and increased insulin sensitivity in addition to increased expression of RAR and other genes (Berry and Noy, 2009). In comparison with other vitamin A metabolizing enzymes responsible in the production of RA, the major enzyme expressed during adipogenesis is ALDH1A1, and ALDH1A1 deficiency was shown to result in impaired adipogenesis (Harrison et al., 2011). Retinal, the substrate of ALDH1A1, is

Figure 6. Structure of human ALDH1A1: Structure of suggested to inhibit PPARG (peroxisome human ALDH1A1 determined using X-ray diffraction (PDB proliferator-activated receptor-gamma) a ID: 4WJ9) (Morgan and Hurley, 2015; Rose et al., 2018). transcription factor known as the master regulator of adipogenesis. Ziouzenkova et al. showed that retinal Mutations is present in rodent fat, binds retinol-binding proteins (CRBP1, RBP4), inhibits adipogenesis and A list of ALDH1A1 mutations in cancer can be suppresses PPARG and RXR responses. In vivo, found in: COSMIC, the Catalogue of Somatic mice lacking the Aldh1a1 resisted diet-induced Mutations in Cancer, obesity and insulin resistance and showed increased https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln energy dissipation. In ob/ob mice, administrating =ALDH1A1. retinal or an Aldh1a1 inhibitor reduced fat and increased insulin sensitivity (Ziouzenkova et al., Implicated in 2007). ALDH1A1 encodes the enzyme ALDH1A1 (also Alcohol-related phenotypes known as retinaldehyde dehydrogenase 1-RALDH1) which is involved in several metabolic processes and Because of its involvement in ethanol metabolism, therefore implicated in various diseases and ALDH1A1 is a candidate for alcohol research. conditions. ALDH1A1 has been implicated in several alcohol- Parkinson's disease related phenotypes, including alcoholism, alcohol- induced flushing, and alcohol sensitivity. Studies Deficiency in ALDH activity, specifically in suggest that low ALDH1A1 activity may contribute ALDH1A1 activity in the substantia nigra, is to alcohol sensitivity and alcohol-induced flushing suggested to lead accumulation of neurotoxic reaction in Caucasians and some Asians. aldehydes and subsequent cell death seen in Polymorphisms located on both coding and promoter Parkinson's disease, and possibly in other regions of ALDH1A1 were found to influence neurodegenerative disorders. ALDH1 mRNA alcoholic predisposition (Spence et al., 2003). expression was reported to be decreased in surviving Kim et al. showed that an evolutionarily conserved neurons of Parkinson's disease patients (Basso et al., GABA synthesis pathway involves Aldh1a1. They 2004). Wey et al. showed that deletion of two found that repeated ethanol exposure reduces GABA isoforms of aldehyde dehydrogenase, Aldh1a1 and co-release from the ventral tegmental area (VTA) Aldh2, which are known to be involved in dopamine dopamine neurons and downregulation of Aldh1a metabolism in the brain, resulted in elevated levels through gene targeting or RNA interference of the neurotoxic aldehydes DOPAL and 4-HNE and increases alcohol consumption in mice. These loss of dopaminergic neurons in the substantia nigra, findings highlight the importance of Aldh1a1 and and caused a Parkinsonian phenotype characterized VTA GABA co-release in moderating alcohol by age-dependent deficits in motor performance consumption (Kim et al., 2015). (Wey et al., 2012). Obesity Cancer Adipogenesis is a process regulated by retinoids. ALDH1A1 has been shown to be related to the Being an ALDH1A1 substrate, retinaldehyde was stemness of both cancer stem cells and normal tissue shown to down-regulate the expression of stem cells. Recent reports reveal that ALDH1 and adipogenesis genes in vitro. In vivo, retinaldehyde specifically ALDH1A1 is a useful cancer stem cell decreased fat levels and increased insulin sensitivity marker that can be used to enrich tumor-initiating

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subpopulations from various cell lines and primary mRNA level and the clinic-pathological features. tumors (Tomita et al., 2016). They found that in human hepatocellular carcinoma, Breast cancer ALDH1A1-overexpressing cells are differentiated cells rather than cancer stem or progenitor cells ALDH1A1 is a breast cancer biomarker for (Tanaka et al., 2015). prediction of tumor progression and its expression is correlated with poor survival (Liu et al., 2014). High Lung cancer ALDH activity and CD44 expression The expression of LGR5 and ALDH1A1 were (ALDHhiCD44+) were found to contribute to found to be closely associated with the metastatic behavior and therapy resistance to breast tumorigenicity, metastasis and poor prognosis of cancer (Croker et al., 2017). non-small cell lung cancer, and LGR5 + cells in non- Colorectal cancer small cell lung cancer are proposed to be the cancer cells with stem cell-like properties due to ALDH1A1 protein expression was found to be the significant correlation between LGR5 increased significantly in colorectal cancer (CRC) and ALDH1A1 (Gao et al., 2015). tissues compared with matched non-tumor adjacent tissues using immunohistochemistry (IHC). Multiple myeloma Therefore, the protein is suggested to be a potential Yang et al. reported that increased expression of prognostic marker in patients with CRC. ALDH1 in multiple myeloma (MM) is a marker of Moreover, in patients with CRC, increased tumor-initiating cells (TICs) that is further expression of the ALDH1A1 protein was shown to associated with chromosomal instability (CIN). be associated with the lymph node metastasis (W. et They found, between the ALDH1 members, al., 2018). ALDH1A1 is most abundantly expressed member in ALDH1A1 expression was found to be associated myeloma and enforced expression of ALDH1A1 in also with features of poor prognosis, including a myeloma cells results in increased clonogenicity, poorly differentiated histology and "right-sidedness" tumor formation in mice, and resistance to myeloma of the primary tumor, and with shorter overall drugs in vitro and in vivo (Y. Yang et al., 2014). survival (Van Der Waals et al., 2018). Ovarian cancer Esophageal cancer (squamous cell Landen Jr et al. showed that in ovarian cancer, carcinoma) ALDH1A1-positive population has properties of Depending on Yang et al., ALDH1A1 cancer stem cells, and this population is associated (high) cancer stem-like cells contribute to the with taxane and platinum resistance. invasion, metastasis and poor outcome of human Additionally, this population was found to be esophageal squamous cell carcinoma. resensitized to chemotherapy both in vitro and in ALDH1A1 high esophageal squamous cell vivo by down-regulation of ALDH1A1 expression carcinoma cells were found to have increased levels (Landen et al., 2010). More recently, Cui et al. of mRNA for VIM (vimentin), matrix showed that in ovarian cancer, DNA damage- metalloproteinase 2, 7, and 9 (MMP2, MMP7 and binding protein 2 (DDB2) suppresses non-cancer MMP9), but decreased the level of CDH1 (E- stem cell to cancer stem cell conversion by cadherin) mRNA, suggesting that epithelial- repressing ALDH1A1 transcription. mesenchymal transition and MMPs may be Mechanistically, DDB2 binds to the ALDH1A1 associated with the high invasive and metastatic gene promoter, enhances the enrichment of histone capabilities of ALDH1A1 high cells (L. Yang et al., H3K27me3, and thereby competes with the 2014). transcription factor CEBPB for binding to this region, and eventually inhibits the promoter activity Gastric cancer of the ALDH1A1 gene (Cui et al., 2018) (Figure 5). The positive rate of ALDH1A1 expression was Pancreatic cancer shown to be 60% in gastric cancer patients (L. Yang et al., 2017), but there was no significant difference ALDH1A1 is a pancreatic stem cell marker and is between survival rates of ALDH1A1-positive and highly enriched in a subpopulation of cells which are ALDH1A1-negative patients (Li et al., 2016; L. extremely resistant to chemotherapy. Furthermore, Yang et al., 2017). ALDH1 is highly enriched in surgical specimens from patients with pancreatic cancer who had Liver cancer undergone preoperative chemo-radiation therapy Tanaka et al. found there was no significant compared to untreated patients (Mizukami et al., difference in the ALDH1A1-mRNA level between 2014). tumorous and non-tumorous tissues of hepatocellular carcinoma patients. In addition, there was no correlation between tumorous ALDH1A1-

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Papillary thyroid carcinoma identified with isotype-specific antibodies. However, when it is the stem cell population, ALDH1A1 levels were significantly higher in Aldefluor assay has to be used to identify ALDH1A1 papillary thyroid carcinoma samples than normal activity (Tomita et al., 2016). Because of the broad thyroid samples and ALDH1A1 overexpression was and varied nature of the interaction between DEAB significantly associated with extrathyroid extension, and ALDH isoenzymes, the results of Aldefluor pT status, pN status and TNM stage. The Kaplan- assay should be interpreted with caution with regard Meier survival analysis shows that high ALDH1A1 to which particular ALDH isoenzymes contribute to expression reflects a poorer lymph node recurrence- the observed fluorescence in the flow cytometry free survival (LN-RFS) and distant recurrence-free assay. Together with Aldefluor assay, other specific survival (DRFS) in papillary thyroid carcinoma measurement methods are needed to determine patients, as compared with patients who have low ALDH1A1 expression and activity in the biological ALDH1A1 expression. Multivariate analysis samples. In this sense, the generation of selective confirmed ALDH1A1 expression as an independent inhibitor(s) for ALDH1A1 appears to be particularly prognostic factor for LN-RFS and DRFS in papillary important. thyroid carcinoma patients (Xing et al., 2014). Prostate cancer References ALDH1A1 is a cancer stem cell marker in prostate Alam M, Ahmad R, Rajabi H, Kharbanda A, Kufe D. MUC1- cancer (Kalantari et al., 2017). Cojoc et al. found that C oncoprotein activates ERK→C/EBPβ signaling and induction of aldehyde dehydrogenase 1A1 in breast cancer the expression of ALDH1A1 is regulated by the cells. J Biol Chem. 2013 Oct 25;288(43):30892-903 WNT signaling pathway. Inhibition of the WNT Basso M, Giraudo S, Corpillo D, Bergamasco B, Lopiano L, pathway led to a decrease in ALDH (+) tumor Fasano M. Proteome analysis of human substantia nigra in progenitor population and to radiosensitization of Parkinson's disease. Proteomics. 2004 Dec;4(12):3943-52 cancer cells (Cojoc et al., 2015). Berry DC, Noy N. All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome To be noted proliferation-activated receptor beta/delta and retinoic acid receptor. Mol Cell Biol. 2009 Jun;29(12):3286-96 Aldefluor assay is widely used to detect ALDH Bhave SV, Hoffman PL, Lassen N, Vasiliou V, Saba L, activity by flow cytometry. This assay is based on Deitrich RA, Tabakoff B. Gene array profiles of alcohol and the conversion of the ALDH substrate BODIPY- aldehyde metabolizing enzymes in brains of C57BL/6 and aminoacetaldehyde (BAAA) to the fluorescence DBA/2 mice Alcohol Clin Exp Res 2006 Oct;30(10):1659- product BODIPY-aminoacetate. Therefore, the level 69 of fluorescence corresponds to the amount of ALDH Cojoc M, Peitzsch C, Kurth I, Trautmann F, Kunz-Schughart activity present in the cell. N,N-diethylamino- LA, Telegeev GD, Stakhovsky EA, Walker JR, Simin K, Lyle benzaldehyde (DEAB), an inhibitor of ALDH S, Fuessel S, Erdmann K, Wirth MP, Krause M, Baumann M, Dubrovska A. Aldehyde Dehydrogenase Is Regulated by activity, is supplied as a negative control for the β-Catenin/TCF and Promotes Radioresistance in Prostate assay. When the assay has been developed, DEAB Cancer Progenitor Cells Cancer Res 2015 Apr was found to be a potent inhibitor of cytosolic ALDH 1;75(7):1482-94 (ALDH1) but not mitochondrial ALDH (ALDH2). Collard F, Vertommen D, Fortpied J, Duester G, Van Because of this, the Aldefluor Assay was thought to Schaftingen E. Identification of 3-deoxyglucosone measure cellular ALDH1A1 activity. However, dehydrogenase as aldehyde dehydrogenase 1A1 (retinaldehyde dehydrogenase 1) Biochimie 2007 recent studies have shown that DEAB inhibits other Mar;89(3):369-73 ALDH isoenzymes and as a result, the Aldefluor assay will detect stem cells with high levels of other Croker AK, Rodriguez-Torres M, Xia Y, Pardhan S, Leong HS, Lewis JD, Allan AL. Differential Functional Roles of ALDH isoenzyme activity, including ALDH1A2, ALDH1A1 and ALDH1A3 in Mediating Metastatic Behavior ALDH1A3, and ALDH2 (Marcato et al., 2011a; and Therapy Resistance of Human Breast Cancer Cells Int Moreb et al., 2012). Morgan et al. analyzed the J Mol Sci 2017 Sep 22;18(10) mechanism underlying DEAB dependent inhibition Cui T, Srivastava AK, Han C, Wu D, Wani N, Liu L, Gao Z, and found that DEAB is a substrate for ALDH3A1, Qu M, Zou N, Zhang X, Yi P, Yu J, Bell EH, Yang SM, ALDH1A1, ALDH1A3, ALDH1B1, ALDH5A1, Maloney DJ, Zheng Y, Wani AA, Wang QE. DDB2 but the turnover rates are so slow that it acts as an represses ovarian cancer cell dedifferentiation by suppressing ALDH1A1 Cell Death Dis 2018 May 1;9(5):561 inhibitor for more rapidly metabolized aldehyde substrates. Additionally, they did not found Gao F, Zhou B, Xu JC, Gao X, Li SX, Zhu GC, Zhang XG, Yang C. The role of LGR5 and ALDH1A1 in non-small cell appreciable turnover of DEAB with either lung cancer: Cancer progression and prognosis Biochem ALDH1A2 or ALDH2, where DEAB behaves as a Biophys Res Commun 2015 Jun 26;462(2):91-8 covalent inhibitor for both isoenzymes (Morgan et Gyamfi MA, Kocsis MG, He L, Dai G, Mendy AJ, Wan YJ. al., 2015). The role of retinoid X receptor alpha in regulating alcohol In IHC analyses, ALDH1A1 can be specifically metabolism J Pharmacol Exp Ther 2006 Oct;319(1):360-8

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Hilton J. Role of aldehyde dehydrogenase in Maring JA, Deitrich RA, Little R. Partial purification and cyclophosphamide-resistant L1210 leukemia Cancer Res properties of human brain aldehyde dehydrogenases J 1984 Nov;44(11):5156-60 Neurochem 1985 Dec;45(6):1903-10 Holmes RS. Comparative and evolutionary studies of Mizukami T, Kamachi H, Mitsuhashi T, Tsuruga Y, vertebrate ALDH1A-like genes and proteins Chem Biol Hatanaka Y, Kamiyama T, Matsuno Y, Taketomi A. Interact 2015 Jun 5;234:4-11 Immunohistochemical analysis of cancer stem cell markers in pancreatic adenocarcinoma patients after neoadjuvant Jackson B, Brocker C, Thompson DC, Black W, Vasiliou K, chemoradiotherapy BMC Cancer 2014 Sep 21;14:687 Nebert DW, Vasiliou V. Update on the aldehyde dehydrogenase gene (ALDH) superfamily Hum Genomics Moreb JS, Ucar D, Han S, Amory JK, Goldstein AS, 2011 May;5(4):283-303 Ostmark B, Chang LJ. 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Targeting aldehyde dehydrogenase cancer stem cells characterization and immunohistochemical localization in in ovarian cancer Mol Cancer Ther 2010 Dec;9(12):3186- the cornea Biochem J 2003 Dec 15;376(Pt 3):615-23 99 Reichert B, Yasmeen R, Jeyakumar SM, Yang F, Thomou Lassen N, Bateman JB, Estey T, Kuszak JR, Nees DW, T, Alder H, Duester G, Maiseyeu A, Mihai G, Harrison EH, Piatigorsky J, Duester G, Day BJ, Huang J, Hines LM, Rajagopalan S, Kirkland JL, Ziouzenkova O. Concerted Vasiliou V. Multiple and additive functions of ALDH3A1 and action of aldehyde dehydrogenases influences depot- ALDH1A1: cataract phenotype and ocular oxidative specific fat formation Mol Endocrinol 2011 May;25(5):799- damage in Aldh3a1(-/-)/Aldh1a1(-/-) knock-out mice J Biol 809 Chem 2007 Aug 31;282(35):25668-76 Rose AS, Bradley AR, Valasatava Y, Duarte JM, Prlic A, Li K, Guo X, Wang Z, Li X, Bu Y, Bai X, Zheng L, Huang Y. Rose PW. NGL viewer: web-based molecular graphics for The prognostic roles of ALDH1 isoenzymes in gastric large complexes Bioinformatics 2018 Nov 1;34(21):3755- cancer Onco Targets Ther 2016 Jun 7;9:3405-14 3758 Li T, Su Y, Mei Y, Leng Q, Leng B, Liu Z, Stass SA, Jiang Spence JP, Liang T, Eriksson CJ, Taylor RE, Wall TL, F. ALDH1A1 is a marker for malignant prostate stem cells Ehlers CL, Carr LG. Evaluation of aldehyde dehydrogenase and predictor of prostate cancer patients' outcome Lab 1 promoter polymorphisms identified in human populations Invest 2010 Feb;90(2):234-44 Alcohol Clin Exp Res 2003 Sep;27(9):1389-94 Liu Y, Lv DL, Duan JJ, Xu SL, Zhang JF, Yang XJ, Zhang Tanaka K, Tomita H, Hisamatsu K, Nakashima T, Hatano Y, X, Cui YH, Bian XW, Yu SC. ALDH1A1 expression Sasaki Y, Osada S, Tanaka T, Miyazaki T, Yoshida K, Hara correlates with clinicopathologic features and poor A. 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promotes tumor growth via glutathione/dihydrolipoic acid- Sox2 in Gastric Cancer Is Associated with Tumor Location dependent NAD(+) reduction Oncotarget 2017 May and Stage PLoS One 2017 Jan 3;12(1):e0169124 8;8(40):67043-67055 Yang W, Wang Y, Wang W, Chen Z, Bai G. Expression of Aldehyde Dehydrogenase 1A1 (ALDH1A1) as a Prognostic Ward RJ, McPherson AJ, Chow C, Ealing J, Sherman DI, Biomarker in Colorectal Cancer Using Yoshida A, Peters TJ. Identification and characterisation of Immunohistochemistry Med Sci Monit 2018 May 7 [revised alcohol-induced flushing in Caucasian subjects Alcohol 2018 Jan 1];24:2864-2872 Alcohol 1994 Jul;29(4):433-8 Yang Y, Zhou W, Xia J, Gu Z, Wendlandt E, Zhan X, Janz Wey MC, Fernandez E, Martinez PA, Sullivan P, Goldstein S, Tricot G, Zhan F. NEK2 mediates ALDH1A1-dependent DS, Strong R. Neurodegeneration and motor dysfunction in drug resistance in multiple myeloma Oncotarget 2014 Dec mice lacking cytosolic and mitochondrial aldehyde 15;5(23):11986-97 dehydrogenases: implications for Parkinson's disease PLoS One 2012;7(2):e31522 Zhao D, Mo Y, Li MT, Zou SW, Cheng ZL, Sun YP, Xiong Y, Guan KL, Lei QY. NOTCH-induced aldehyde Xing Y, Luo DY, Long MY, Zeng SL, Li HH. High ALDH1A1 dehydrogenase 1A1 deacetylation promotes breast cancer expression correlates with poor survival in papillary thyroid stem cells J Clin Invest 2014 Dec;124(12):5453-65 carcinoma World J Surg Oncol 2014 Feb 3;12:29 Ziouzenkova O, Orasanu G, Sharlach M, Akiyama TE, Yang CK, Wang XK, Liao XW, Han CY, Yu TD, Qin W, Zhu Berger JP, Viereck J, Hamilton JA, Tang G, Dolnikowski GZ, Su H, Yu L, Liu XG, Lu SC, Chen ZW, Liu Z, Huang KT, GG, Vogel S, Duester G, Plutzky J. Retinaldehyde Liu ZT, Liang Y, Huang JL, Xiao KY, Peng MH, Winkle CA, represses adipogenesis and diet-induced obesity Nat Med O'Brien SJ, Peng T. Aldehyde dehydrogenase 1 (ALDH1) 2007 Jun;13(6):695-702 isoform expression and potential clinical implications in hepatocellular carcinoma PLoS One 2017 Aug van der Waals LM, Borel Rinkes IHM, Kranenburg O. 8;12(8):e0182208 ALDH1A1 expression is associated with poor differentiation, 'right-sidedness' and poor survival in human colorectal Yang L, Ren Y, Yu X, Qian F, Bian BS, Xiao HL, Wang WG, cancer PLoS One 2018 Oct 11;13(10):e0205536 Xu SL, Yang J, Cui W, Liu Q, Wang Z, Guo W, Xiong G, Yang K, Qian C, Zhang X, Zhang P, Cui YH, Bian XW. This article should be referenced as such: ALDH1A1 defines invasive cancer stem-like cells and predicts poor prognosis in patients with esophageal Tunçer S, Çamlca R, Yilmaz I.. ALDH1A1 (Aldehyde squamous cell carcinoma Mod Pathol 2014 May;27(5):775- Dehydrogenase 1 family member A1). Atlas Genet 83 Cytogenet Oncol Haematol. 2020; 24(3):102-111. Yang L, Xu JF, Kang Q, Li AQ, Jin P, Wang X, He YQ, Li N, Cheng T, Sheng JQ. Predictive Value of Stemness Factor

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Gene Section Review

OOEP (Oocyte expressed protein) Luigi Cristiano Aesthetic and medical biotechnologies research unit, Prestige, Terranuova Bracciolini, Italy; [email protected] Published in Atlas Database: March 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/OOEPID71121ch6q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70677/03-2019-OOEPID71121ch6q13.pdf DOI: 10.4267/2042/70677

Abstract Identity Oocyte expressed protein, alias OOEP, is a Other names: C6orf156, Em:AC019205.2, component of the subcortical maternal complex KHDC2, FLOPED, HOEP19, KH homology (SCMC) that play its roles in oocytes and in early domain containing 2, KH homology domain- stages of embryogenesis. In this review it is done an containing protein 2, KH Homology Domain insight on its DNA, its RNA, its protein encoded and Containing 2, oocyte and embryo protein 19, oocyte on the diseases where OOEP is involved. expressed protein homolog (dog), oocyte- and Keywords embryo-specific protein 19, MOEP19, OEP19 OOEP; Oocyte expressed protein; subcortical HGNC (Hugo): OOEP maternal complex, SCMC, embryogenesis, zygote Location: 6q13

Figure. 1. OOEP gene, transcript and splicing variants/isoforms. The figure shows the locus on chromosome 6 of the OOEP gene, its transcript and its alternative splicing/isoforms (blue). The primary transcript is OOEP-201 mRNA (orange), but also EEF1G-202/203 variants seem be able to codify a protein (reworked from https://www.ncbi.nlm.nih.gov/gene/1937; http://grch37.ensembl.org; www.genecards.org)

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Figure.2 OOEP protein structure. (1) Primary structure of OOEP with emphasis on its main domain; (2) protein-protein interactions in the SCMC complex (reworked from Babbere et al., 2016).

Gene Gene name RefSeq Locus Location Start End Lenght (nt) AL499605.1-201 OOEP pseudogene ENST00000604628.1 1p21.1 Chrom. 1 106544342 106544744 403 AL355333.1 OOEP pseudogene ENSG00000270234 10p14 Chrom. 10 8724010 8724288 279

Table.1 OOEP pseudogenes (reworked from https://www.ncbi.nlm.nih.gov/gene/1937)

and gains another distant element. All three DNA/RNA transcript variants encode a protein. Description Pseudogene OOEP, alias oocyte expressed protein, is a protein For OOEP are known some pseudogenes that are coding gene that starts at 73,368,555 nt and ends at classified as processed pseudogenes and are listed in 73,369,792nnt from qter and with a length of 1238 Table 1. bp. The current reference sequence is NC_000006.12 Protein and contain 3 exons. It is proximal to KHDC3L (KH domain containing 3 Description like, subcortical maternal complex member) gene The canonical sequence for OOEP protein (RefSeq and to RPL39P3 (ribosomal protein L39 pseudogene NP_001073976) counts 149 amino acids and has a 3) gene. Around the genomic locus of OOEP take molecular weight of 17.17 kDa and a theoretical pI place different promoter or enhancer transcriptional of 6.59. Contains a KH-domain, a typical domain of elements. the type I superfamily of RNA binding proteins Two strong elements are closer to the sequence of (Herr et al., 2008), that could mediate RNA OOEP gene and are located at +0.3 kb and at -27.3 transcript regulation during the oogenesis and early kb respectively. embryogenesis stages. Transcription There are known other two isoforms produced by alternative splicing: the isoform OOEP-202 (UniRef, OOEP transcript is 689 bp long with a reference F2Z364) is formed by 94 residues and has a sequence reported in GeneBank as NM_001080507. molecular weight of 10.72 kDa, while the isoform It lacks the 5' UTR, the CDS is extended from 1 to OOEP-203 (UniRef, C9J915) counts 67 amino acids 450 nt and the 3' UTR is extended in the remaining and has 7.70 kDa of molecular weight. part of the sequence, i.e. from 451 to 689 nt. Splice variants for OOEP was observed: the main Expression reference variant is OOEP (OOEP-201) and the OOEP, as the others factors of the subcortical others are OOEP-202 and OOEP-203 (Figure.1). maternal complex (SCMC), is uniquely expressed in OOEP-202, 1007 nt long, is formed by a fragment of mammalian oocytes and in early embryo (Bebbere et exon 3, by the entire exon 2, it lacks the first exon al., 2016). However, some authors found mouse and gains a forth distant element. OOEP-203, 964 nt OOEP transcripts also in ovary and thymus, although long, lacks exons 3 and 1, maintains the entire exon2 the protein could not be detected. This may suggest that the transcript remains untranslated (Herr et al.,

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2008) and perhaps plays a regulatory function. The Homology human OOEP mRNA was found in pituitary gland OOEP is highly and abundant conserved in many (Herr et al., 2008; Carninci and Hayashizaki, 1999), species and its homology between the species is placenta (https://www.ncbi.nlm.nih.gov/gene) and reported in Table.2 testis, where it was overexpressed DNA PROT (https://www.gtexportal.org/home/gene/ENSG0000 Symbol Organism Species Similarit Similarit

0203907; https://genevisible.com/ y (%) y (%) tissues/HS/UniProt/A6NGQ2). Human H.sapiens OOEP 100 100 It was also found in traces in ovary, endometrium, Chimpanzee P.troglodytes prostate, salivary gland, adrenal, appendix, brain, OOEP 99.3 99.3 digestive system and related organs (esophagus, stomach, duodenum, small intestine, colon, gall Macaco M.mulatta OOEP 96.0 95.3 bladder, liver, pancreas), lung, fat cells, heart, Wolf C.lupus OOEP 78.7 71.8 spleen, thyroid and urinary bladder (from Cattle B.taurus OOEP 77.4 68.6 https://www.ncbi. nlm.nih.gov/gene). Mouse M.musculus OOEP 68.2 54.6 Table.2 OOEP homology (reworked from Localisation https://www.ncbi.nlm.nih.gov/homologene?) OOEP is located in the cytoplasm. Mutations Function The genomic alterations observed include the OOEP is a component of the subcortical maternal formation of novel fusion genes as EEF1G/OOEP complex (SCMC) that includes at least other three (acute lymphoblastic leukemia/lymphoblastic proteins, i.e. KHDC3L (also known as KH domain lymphoma), EXOC2/OOEP (bladder transitional containing protein 3, FILIA), NLRP5 (also called cell carcinoma), FAM19A2/OOEP (breast Maternal Antigen That Embryo Requires, MATER) adenocarcinoma), KHDC1/OOEP, OOEP/ EIF3A, and TLE6 (also known as Transducin-Like Enhancer RERE/OOEP (prostate adenocarcinoma) and of Split 6). SENP6/OOEP (prostate adenocarcinoma) These proteins are expressed by maternal effect (http://atlasgeneticsoncology.org//Bands/6q13.html) genes (MEGs) exclusively in oocytes and early , however there are no experimental data yet to embryos and are physically bound together in the understand the impact on cellular behaviour and so SCMC complex. the implications in cancer of these fusion genes. Also only a mutation on one of them, such as TLE6, induces instability of the complex and may be a Implicated in cause of human female infertility and earliest human embryonic lethality (Bebbere et al., 2016; Alazami Top note et al., 2015; Zhu et al., 2015; Bebbere et al., 2014). OOEP is a maternal-effect gene that is expressed in OOEP plays an essential role for zygote progression zygote and in early stages of embryo development. beyond the first embryonic cell divisions (Bebbere et It is linked with female infertility, however there is al., 2014) and it is hypotized that it could play a role some evidence of its involvement in cancers. We in the formation/stabilization of the oocyte review the diseases in which OOEP gene showed cytoskeleton, called oocyte cytoplasmic lattices overexpression, upregulation or aberrant fusion with (CPLs) and also it could be involved in the other genes. Anyhow some authors found a organization and regulation of the translational downregulation of OOEP in ovarian cancer patient machinery through the interaction between SCMC samples (Veskimäe et al., 2018), in colon cancer complex with other protein and/or protein complexes (Penrose et al., 2019) and in prostate cancer cells (Lu (Bebbere et al., 2016; Tashiro et al., 2010). et al., 2015). In addition, OOEP could be involved in RNA t(6;11)(q13;q12) EEF1G/OOEP degradation during oocyte maturation and in the Disease early stages of embryogenesis (Wang et al., 2012) Acute lymphoblastic leukemia/lymphoblastic and it could be directly or indirectly involved in the lymphoma (Atak et al, 2013) binding of the mRNAs and in their correct subcellular localization (Bebbere et al., 2016). In Hybrid/Mutated gene mouse oocytes was found that OOEP may T-cell acute lymphoblastic leukemia (T-ALL) participate in the regulation of genome stability (He affects about 15% of pediatric patients and 25% of et al., 2018), but it is not confirmed in humans yet. adult patients of total ALL cases. It is an agressive tumor characterized by the accumulation of multiple genomic mutations and chromosomal aberrations, such as frequently chromosomal translocations, that

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bring to the formation of many in-frame fusion genes Alazami AM, Awad SM, Coskun S, Al-Hassan S, Hijazi H, encoding the respective chimeric and oncogenic Abdulwahab FM, Poizat C, Alkuraya FS. TLE6 mutation causes the earliest known human embryonic lethality. proteins (Atak et al., 2013). Among all these Genome Biol. 2015 Nov 5;16:240 chromosomal aberrations it was found also the Atak ZK, Gianfelici V, Hulselmans G, De Keersmaecker K, fusion gene 5' EEF1G / 3' OOEP deriving by the Devasia AG, Geerdens E, Mentens N, Chiaretti S, Durinck genomic translocation and fusion of a part of OOEP K, Uyttebroeck A, Vandenberghe P, Wlodarska I, Cloos J, gene, situated on chromosome 6, with a portion of Foà R, Speleman F, Cools J, Aerts S. Comprehensive EEF1G gene, located on chromosome 11. This leads analysis of transcriptome variation uncovers known and novel driver events in T-cell acute lymphoblastic leukemia. to the know but not still well-characterized PLoS Genet. 2013;9(12):e1003997 translocation t(6;11)(q13;q12) EEF1G/OOEP. Bebbere D, Ariu F, Bogliolo L, Masala L, Murrone O, Human female infertility/ early Fattorini M, Falchi L, Ledda S. Expression of maternally embryo lethality derived KHDC3, NLRP5, OOEP and TLE6 is associated with oocyte developmental competence in the ovine Disease species. BMC Dev Biol. 2014 Nov 25;14:40 Aberrant expression of SCMC members, such as Bebbere D, Masala L, Albertini DF, Ledda S. The OOEP, could compromise the fertility in women but subcortical maternal complex: multiple functions for one also could be linked to abnormalities in biological structure? J Assist Reprod Genet. 2016 preimplantation embryo development and in early Nov;33(11):1431-1438 lethality of the human embryos and so cover a Carninci P, Hayashizaki Y. High-efficiency full-length cDNA significant role both in female inability to get cloning. Methods Enzymol. 1999;303:19-44 pregnant and in failure of the development of He DJ, Wang L, Zhang ZB, Guo K, Li JZ, He XC, Cui QH, implanted embryo after in vitro reproductive Zheng P. Maternal gene Ooep may participate in assistance procedures (Bebbere et al., 2016; Alazami homologous recombination-mediated DNA double-strand break repair in mouse oocytes Zool Res 2018 Nov et al., 2015; Zhu et al., 2015; Zhang et al., 2008). 18;39(6):387-395 To effort these considerations, an experiment in Herr JC, Chertihin O, Digilio L, Jha KN, Vemuganti S, mouse demonstrated that a lack of OOEP gene Flickinger CJ. Distribution of RNA binding protein MOEP19 (OOEP -/- knockout mice) causes complete in the oocyte cortex and early embryo indicates pre- infertility and disorganization/abnormalities in patterning related to blastomere polarity and trophectoderm oocyte cytoplasmic lattices (CPLs). However, Ooep- specification Dev Biol 2008 Feb 15;314(2):300-16 null mice females grew to adulthood and showed no Jiang L, Huang J, Higgs BW, Hu Z, Xiao Z, Yao X, Conley apparent abnormalities except the infertility (Tashiro S, Zhong H, Liu Z, Brohawn P, Shen D, Wu S, Ge X, Jiang et al., 2010). Y, Zhao Y, Lou Y, Morehouse C, Zhu W, Sebastian Y, Czapiga M, Oganesyan V, Fu H, Niu Y, Zhang W, Streicher Osteosarcoma K, Tice D, Zhao H, Zhu M, Xu L, Herbst R, Su X, Gu Y, Li S, Huang L, Gu J, Han B, Jallal B, Shen H, Yao Y. Genomic Some authors found OOEP gene upregulated in Landscape Survey Identifies SRSF1 as a Key Oncodriver in osteosarcoma cells (Li et al., 2017). Small Cell Lung Cancer PLoS Genet 2016 Apr 19;12(4):e1005895 Small cell lung carcinoma Li S, Dong Y, Wang K, Wang Z, Zhang X. Transcriptomic The expression of OOEP is increased in small cell analyses reveal the underlying pro-malignant functions of lung carcinoma (Jiang et al., 2016). PTHR1 for osteosarcoma via activation of Wnt and angiogenesis pathways J Orthop Surg Res 2017 Nov Testis cancer 9;12(1):168 Some databases reported that the expression of Lu Y, Li J, Cheng J, Lubahn DB. Messenger RNA profile OOEP is increased in testis cancer analysis deciphers new Esrrb responsive genes in prostate (https://www.proteinatlas.org/ENSG00000203907- cancer cells BMC Mol Biol 2015 Dec 1;16:21 OOEP/pathology; https://genevisible.com/cancers/ Penrose HM, Cable C, Heller S, Ungerleider N, Nakhoul H, HS/UniProt/A6NGQ2) but is not clear if also protein Baddoo M, Hartono AB, Lee SB, Burow ME, Flemington EF, can be displayed. Crawford SE, Savkovic SD. Loss of Forkhead Box O3 Facilitates Inflammatory Colon Cancer: Transcriptome Profiling of the Immune Landscape and Novel Targets Cell Thyroid cancer Mol Gastroenterol Hepatol 2019;7(2):391-408 One database reported high levels for the presence of Tashiro F, Kanai-Azuma M, Miyazaki S, Kato M, Tanaka T, OOEP protein in thyroid cancer although its Toyoda S, Yamato E, Kawakami H, Miyazaki T, Miyazaki J. expression level in this cancer type was reported to Maternal-effect gene Ces5/Ooep/Moep19/Floped is be lower (https://www.proteinatlas.org/ essential for oocyte cytoplasmic lattice formation and ENSG00000203907-OOEP/pathology).

embryonic development at the maternal-zygotic stage transition Genes Cells 2010 Aug;15(8):813-28 Veskimäe K, Scaravilli M, Niininen W, Karvonen H, Jaatinen References S, Nykter M, Visakorpi T, Mäenpæ J, Ungureanu D, Staff S.

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Expression Analysis of Platinum Sensitive and Resistant family suggests a role in human preimplantation Epithelial Ovarian Cancer Patient Samples Reveals New development PLoS One 2008 Jul 23;3(7):e2755 Candidates for Targeted Therapies Transl Oncol 2018 Oct;11(5):1160-1170 Zhu K, Yan L, Zhang X, Lu X, Wang T, Yan J, Liu X, Qiao J, Li L. Identification of a human subcortical maternal Wang J, Xu M, Zhu K, Li L, Liu X. The N-terminus of FILIA complex Mol Hum Reprod 2015 Apr;21(4):320-9 forms an atypical KH domain with a unique extension involved in interaction with RNA PLoS One This article should be referenced as such: 2012;7(1):e30209 Cristiano L. OOEP (Oocyte expressed protein). Atlas Zhang P, Dixon M, Zucchelli M, Hambiliki F, Levkov L, Genet Cytogenet Oncol Haematol. 2020; 24(3):112-116. Hovatta O, Kere J. Expression analysis of the NLRP gene

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Gene Section Review

EEF1D (eukaryotic translation elongation factor 1 delta) Luigi Cristiano Aesthetic and medical biotechnologies research unit, Prestige, Terranuova Bracciolini, Italy. [email protected]; [email protected] Published in Atlas Database: May 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/EEF1DID43240ch8q24.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70678/05-2019-EEF1DID43240ch8q24.pdf DOI: 10.4267/2042/70678

Keywords Abstract EEF1D; Eukaryotic translation elongation factor 1 Eukaryotic translation elongation factor 1 delta, alias delta; Translation; Translation elongation factor; EEF1D, is a protein-coding gene that plays a role in protein synthesis; cancer; oncogene; cancer marker the elongation step of translation and considering its importance it is found frequently overexpressed in Identity human cancer cells. Other names: EF-1D, EF1D, , FLJ20897, FP1047 This review collects the data on DNA/RNA, on the protein encoded and on the diseases where EEF1D is HGNC (Hugo): EEF1D involved. Location: 8q24.3

Figure. 1. EEF1D gene and splicing variants/isoforms. The figure shows the locus on chromosome 8 of the EEF1D gene (reworked from https://www.ncbi.nlm.nih.gov/gene; http://grch37.ensembl.org; www.genecards.org)

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Lenght Lenght MW Name Variant RefSeq (1) Transcript ID Exons Type Isoform Alias RefSeq (2) pI (bp) (aa) (kDa) EEF1D- ENST0000042 protein Isoform Var.3 NM_001130053 9 2356 - NP_001123525 647 71.42 6.02 204 3316.6 coding 1 EEF1D- 205 ENST0000044 protein Isoform Var.1 NM_032378 10 2473 - NP_115754 647 71.42 6.02 (EEF1D- 2189.6 coding 1 001) EEF1D- ENST0000031 protein Isoform Var.6 NM_001130057 8 1458 - NP_001123529 281 31.12 4.90 201 7198.10 coding 2 EEF1D- ENST0000041 protein Isoform Var.5 NM_001130055 9 1427 - NP_001123527 281 31.12 4.90 203 9152.6 coding 2 EEF1D- 225 (EE ENST0000052 protein - - 8 1311 - - - 281 - - F1D- 9272.5 coding 006) Isoform EEF1D- Var.9 NM_001289950 1428 - NP_001276879 281 31.12 4.90 202 (EE ENST0000039 protein 2 8 F1D- 5119.7 coding Isoform Var.2 NM_001960 1251 - NP_001951 281 31.12 4.90 002) 2 EEF1D- 207 ENST0000052 protein - - 8 1084 - - - 257 - - (EEF1D- 4624.5 coding 053) EEF1D- 218 (EE ENST0000052 protein Isoform Var.8 NM_001195203 8 1194 - NP_001182132 262 29.07 4.91 F1D- 6838.5 coding 5 005) Isoform Var.7 NM_001130056 1179 - NP_001123528 257 28.56 4.81 4 EEF1D- 223 (EE ENST0000052 protein Isoform Var.10 NM_001317743 7 1176 - NP_001304672 257 28.56 4.81 F1D- 8610.5 coding 4 004) Isoform Var.11 NM_001330646 1386 - NP_001317575 257 28.56 4.81 4 EEF1D- 246 ENST0000053 protein - - 8 2387 - - - 697 - - (EEF1D- 2741.5 coding 007) EEF1D- ENST0000061 protein - - 10 2238 - - - 631 - - 256 8139.2 coding EEF1D- 232 ENST0000053 protein - - 5 1217 - - - 166 - - (EEF1D- 0445.5 coding 017) EEF1D- 253 ENST0000053 protein - - 8 1001 - - - 261 - - (EEF1D- 4380.5 coding 048) EEF1D- 216 ENST0000052 protein - - 1 996 - - - 300 - - (EEF1D- 6710.1 coding 040) EEF1D- 239 ENST0000053 protein - - 3 926 - - - 179 - - (EEF1D- 1670.5 coding 034) EEF1D- 230 ENST0000053 protein - - 5 853 - - - 204 - - (EEF1D- 0191.5 coding 032) EEF1D- ENST0000053 protein - - 7 842 - - - 204 - - 247 3204.5 coding

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(EEF1D- 047) EEF1D- 238 ENST0000053 protein - - 7 840 - - - 238 - - (EEF1D- 1621.5 coding 020) EEF1D- 208 ENST0000052 protein - - 2 828 - - - 180 - - (EEF1D- 4883.1 coding 037) EEF1D- 237 ENST0000053 protein - - 2 813 - - - 257 - - (EEF1D- 1281.1 coding 035) EEF1D- 244 ENST0000053 protein - - 2 791 - - - 39 - - (EEF1D- 2543.1 coding 033) EEF1D- 236 ENST0000053 protein - - 7 787 - - - 198 - - (EEF1D- 1218.5 coding 046) EEF1D- 215 ENST0000052 protein - - 6 770 - - - 63 - - (EEF1D- 6340.5 coding 039) EEF1D- 245 ENST0000053 protein - - 3 761 - - - 190 - - (EEF1D- 2596.5 coding 042) EEF1D- 248 ENST0000053 protein - - 7 758 - - - 168 - - (EEF1D- 3494.5 coding 045) EEF1D- 234 ENST0000053 protein - - 6 749 - - - 210 - - (EEF1D- 0616.5 coding 011) EEF1D- 249 ENST0000053 protein - - 5 633 - - - 137 - - (EEF1D- 3749.5 coding 052) EEF1D- 252 ENST0000053 protein - - 5 617 - - - 187 - - (EEF1D- 4377.5 coding 049) EEF1D- 233 ENST0000053 protein - - 3 616 - - - 84 - - (EEF1D- 0545.5 coding 027) EEF1D- 241 ENST0000053 protein - - 2 614 - - - 35 - - (EEF1D- 1931.1 coding 024) EEF1D- 210 ENST0000052 protein - - 2 610 - - - 39 - - (EEF1D- 5223.1 coding 050) EEF1D- 228 ENST0000052 protein - - 3 600 - - - 146 - - (EEF1D- 9832.5 coding 043) EEF1D- ENST0000053 protein - - 3 583 - - - 129 - - 231 0306.5 coding

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EEF1D (eukaryotic translation elongation factor 1 delta) Cristiano L

(EEF1D- 041) EEF1D- 211 ENST0000052 protein - - 3 559 - - - 81 - - (EEF1D- 5261.5 coding 031) EEF1D- 220 ENST0000052 protein - - 4 558 - - - 21 - - (EEF1D- 8303.5 coding 026) EEF1D- 255 ENST0000053 protein - - 4 555 - - - 68 - - (EEF1D- 4804.5 coding 029) EEF1D- 222 ENST0000052 protein - - 2 553 - - - 157 - - (EEF1D- 8519.1 coding 036) EEF1D- 254 ENST0000053 protein - - 4 538 - - - 31 - - (EEF1D- 4475.5 coding 030) EEF1D- 214 ENST0000052 protein - - 3 535 - - - 53 - - (EEF1D- 6135.5 coding 038) EEF1D- 229 ENST0000053 protein - - 3 533 - - - 156 - - (EEF1D- 0109.5 coding 014) EEF1D- 242 ENST0000053 protein - - 3 506 - - - 49 - - (EEF1D- 1953.5 coding 021) EEF1D- 226 ENST0000052 protein - - 6 473 - - - 139 - - (EEF1D- 9516.5 coding 019) EEF1D- 227 ENST0000052 protein - - 3 424 - - - 119 - - (EEF1D- 9576.5 coding 015) EEF1D- 243 ENST0000053 protein - - 4 419 - - - 99 - - (EEF1D- 2400.1 coding 016) EEF1D- 213 ENST0000052 protein - - 2 367 - - - 36 - - (EEF1D- 6133.1 coding 022) EEF1D- 209 ENST0000052 protein - - 3 343 - - - 62 - - (EEF1D- 4900.1 coding 044) EEF1D- 221 ENST0000052 protein - - 3 308 - - - 36 - - (EEF1D- 8382.1 coding 013) EEF1D- ENST0000052 nonsense - - 8 957 ------206 4397.5 md EEF1D- ENST0000052 nonsense - - 8 861 ------224 9007.5 md EEF1D- ENST0000053 nonsense - - 7 831 ------250 3833.5 md

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EEF1D- ENST0000053 processed - - 4 589 ------240 1770.5 transcript EEF1D- ENST0000052 retained - - 4 3718 ------219 7741.5 intron EEF1D- ENST0000052 retained - - 6 1246 ------217 6786.5 intron EEF1D- ENST0000052 retained - - 3 907 ------212 5695.5 intron EEF1D- ENST0000053 retained - - 6 817 ------251 4232.5 intron EEF1D- ENST0000053 retained - - 5 688 ------235 0848.5 intron Table.1 Alterative splicing variants and isoforms of EEF1D. (reworked from http://grch37.ensembl.org; ttps://www.ncbi.nlm.nih.gov; https://web.expasy.org/protparam/; https://www.uniprot.org) ncRNA = non-coding RNA; nonsense md = nonsense mediated decay; (?) = undetermined; MW = molecular weight; pI = theoretical pI

involved in human cancers or in other diseases. DNA/RNA Especially EEF1DP3 was found in some genomic rearrangements with the formation of hybrid genes Description among which the most studied is EEF1DP3/FRY EEF1D (Eukaryotic Translation Elongation Factor 1 (Kim et al., 2015). delta) is a protein-coding gene that starts at 143,579,722 nt and ends at 143,597,675 nt from pter. Protein It has a length of 17,954 bp and the current reference sequence is NC_000008.11. Description It is proximal to the NAPRT (nicotinate phospho- The eukaryotic translation elongation factor 1 delta ribosyl-transferase domain containing 1) gene and (alias eEF1D, eEF1delta;, eEF1Bdelta;) is a subunit TIGD5 (tigger transposable element derived 5) gene. of the macromolecular eukaryotic translation Around the genomic locus of EEF1D there are elongation factor-1 complex (alias eEF1, also called different promoter or enhancer transcriptional eEF1H), a high-molecular-weight form made up of elements. an aggregation of different protein subunits: EEF1A Two strong of these elements are closer to the (alias eEF1α), EEF1B2 (alias eEF1Β, eEF1Bα, sequence of EEF1D gene and are located at +1.6 kb eEF1B2), EEF1G (alias eEF1γ, heEF1γ, eEF1Bγ), and at -1.2 kb respectively. EEF1D and valyl t-RNA synthetase ( VARS). Transcription eEF1H protein complex plays a central role in Several alternative splicing transcript variants for peptide elongation during eukaryotic protein EEF1D were observed and they encode multiple biosynthesis, in particular for the delivery of eEF1D isoforms. Their main characteristics are aminoacyl-tRNAs to the ribosome mediated by the reported in Table.1 . The main reference sequence is hydrolysis of GTP. NM_032378.5 that corresponds to the variant 1 of In fact, during the translation elongation step, the EEF1D mRNA, alias EEF1D-205 or EEF1D-001, inactive GDP-bound form of eEF1A (eEF1A-GDP) and it is 2,473 bp long. The 5'UTR counts 459 nt, the is converted to its active GTP-bound form (eEF1A- CDS is extended from 460 to 2,403 nt, while the GTP) by eEF1BGD-complex mediated the GTP 3'UTR covers the last 70 nt. hydrolysis. Thus eEF1BGD-complex acts as a guanine nucleotide exchange factor (GEF) Pseudogene regenerating eEF1A-GTP for the successive According to Entrez Gene, the analysis of the human elongation cycle. genome revealed the presence of several The physiological role of eEF1D in the translation pseudogenes for EEF1D (Table.2) classified as context is still not well defined, however eEF1D processed pseudogenes and probably originated by seems to strictly collaborate with eEF1B in the retrotransposition. conversion of eEF1A from its inactive GDP-bound If these elements have any regulatory role in the form to its active GTP-bound form and so it covers expression of the respective gene as described for a role as a guanine nucleotide exchange factor (GEF) others (Hirotsune et al., 2003), is only speculation in for eEF1A (Le Sourd et al., 2006; Browne and the absence of experimental evidence. Proud, 2002). Little more characterized are EEF1DP3 and EEF1DP4 pseudogenes respect the others. What is known is that these two pseudogenes are probably

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Gene na Gene Locatio Lengh Gene RefSeq Locus Start End Main diseases/td> Reference me ID n t (nt) EEF1D Large B-cell lymphoma (?) - EEF1D 12603 NC_000 Chromos 19p13.1 pseudoge 14070325 14071304 980 P1 7 019.10 ome 19 2 ne 1 Myeloid leukemia (?) - EEF1D EEF1D 44242 NC_000 Chromos pseudoge 9q22.31 92836766 92837741 976 Melanoma (?) - P2 9 009.12 ome 9 ne 2 Erho et al., Prostate carcinoma 2012 Kim et al., Breast carcinoma 2015 Shahba et Ankylosing spondylitis al., 2018 Melanoma (?) - EEF1D EEF1D 19654 NC_000 Chromos pseudoge 13q13.1 31846783 31959584 112802 Non-small cell lung cancer (?) - P3 9 013.11 ome 13 ne 3 Multiple sclerosis (?) - Large B-cell lymphoma cell lines (SUDHL4, Toledo, OCI- - Ly3)(?) Lung adenocarcinoma (?) - Epidermolysis Bullosa Simplex

(?) Glioma (?) - EEF1D EEF1D 44232 NC_000 Chromos Breast carcinoma (?) - pseudoge 7q11.21 64862951 64864450 1500 P4 5 007.14 ome 7 ne 4 Primary myelofibrosis (?) - Osteosarcoma (?) - EEF1D Stefansso EEF1D 44225 NC_000 Chromos 12858006 12858095 pseudoge 6q22.33 888 Breast carcinoma n et al., P5 8 006.12 ome 6 5 2 ne 5 2011 EEF1D EEF1D 64435 NC_000 Chromos pseudoge 1p36.32 4175463 4175899 437 - - P6 7 001.11 ome 1 ne 6 EEF1D EEF1D 10042 NC_000 Chromos pseudoge 17q23.3 63636601 63637110 510 - - P7 2656 017.11 ome 17 ne 7 EEF1D EEF1D 28323 NC_000 Chromos pseudoge 11q12.3 62169219 62169827 609 - - P8 6 011.10 ome 11 ne 8 Table.2 EEF1D pseudogenes (reworked from https://www.ncbi.nlm.nih.gov/gene/1937; https://www.targetvalidation.org; https://www.ncbi.nlm.nih.gov/geoprofiles/) [ (?) ] uncertain; [ - ] no reference

There are known four isoforms produced by GEF) while in the amino half terminal there are a alternative splicing: the isoform 1 (RefSeq highly-conserved leucine-rich zipper-like region (aa NP_001123525 or NP_115754), also called eEF1DL 184-225), a basic region (aa 272-294) and a nuclear or eEF1Bdelta;L, is the longest isoform that also has localization signal (NLS)(Kaitsuka et al., 2015; been chosen as the canonical sequence and it is Kaitsuka et al., 2011; Sanders et al., 1993). The basic formed by 647 residues. region seems to be involved in DNA binding while It is found in the eEF1H protein complex and it the leucine zipper region may be a protein interaction shows many domains: in the carboxyl half terminal domain. there are an acidic region and an EF-1 guanine However, the exact functional role of these regions nucleotide exchange domain (EF1-GNE domain / is unclear (Kaitsuka et al., 2015).

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Figure.2 eEF1D protein isoforms. Graphical representation of eEF1D protein isoforms with the highlight of the main verified post-translational modifications (reworked from Kaitsuka et al., 2015; Kaitsuka et al., 2011; http://grch37.ensembl.org; https://www.ncbi.nlm.nih.gov; https://www.uniprot.org/uniprot/P29692; http://bioinf.umbc.edu/dmdm/gene_prot_page.php).

The N-terminal domain of eEF1D interacts with the NP_001123525) and interact with the valyl -tRNA NT-eEF1G domain of eEF1G (Cao et al., 2014; synthetase (Val-RS)(Le Sourd et al., 2006; Bec et al., Mansilla et al., 2002; Janssen et al., 1994) but there 1994). are no interactions between eEF1D and eEF1B EEF1D interacts with SIAH1, an E3 ubiquitin (Sheu and Traugh, 1997), although different protein ligase involved in the regulation of cell cycle, interactional models were proposed (Le Sourd et al., tumorigenesis and also in the initiation of 2006; Jiang et al.,2005; Sheu and Traugh, 1999; neurodegenerative diseases. Minella et al., 1998). Is reported that the overexpression of EEF1D is The long isoform of eEF1D (eEF1DL) interacts with linked with an increase in SIAH-1 levels due to the HSF1 and NFE2L2 (NRF2) proteins into the nucleus inhibition of its autoubiquitination and thus of its (Kaitsuka et al., 2011; https://www.genecards.org) degradation (Wu et al., 2011). and regulates induction of heat-shock-responsive In addition, EEF1D is an interaction partner of genes, such as HSPA6, CRYAB, DNAJB1 and HO- kinectin that function as the membrane anchor for 1, through the association with the heat shock EEF1D on the endoplasmic reticulum (Ong et al., transcription factors and with a direct DNA-binding 2003) at heat shock promoter elements (HSE) (Kaitsuka et Post-translational modifications. Some post- al., 2015; Kaitsuka et al., 2011; translational modifications are observed, such as https://www.uniprot.org/uniprot/P29692). phosphorylation, acetylation and succinylation The isoform 2, with 281 amino acids, is smaller and, (https://www.ncbi.nlm.nih.gov). eEF1D can be as the isoform 1, it is a multi-domain protein which hyperphosphorylated and the phosphorylations are consists of three main domains: from the amino to made by some protein kinases, including casein carboxyl half terminal there are an N-terminal kinase 2 (Gyenis et al., 2011; Browne and Proud, leucine zipper domain, a C-terminal acidic region 2002) and cyclin-dependent kinase 1 ( CDK1) and a C-terminal domain that shows GDP/GTP (Kawaguchi et al., 2003). In particular, CDK1 exchange activity (GEF)( Kaitsuka et al., 2015; phosphorylates EEF1D at Ser-133 (Kawaguchi et al., Kaitsuka et al., 2011). The roles of the isoform 4 and 2003). isoform 5 are still undefined. In addition, eEF1D can be found All isoforms have many interaction surface points hyperphosphorylated by viral protein kinases after with the eukaryotic translation elongation factor 1 alpha-, beta-, and gammaherpesviruses infections alpha (eEF1A) protein (Kawaguchi et al., 2003). (https://www.ncbi.nlm.nih.gov/protein/

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Figure 3. The translation elongation mechanism. The active form of eukaryotic translation elongation factor 1 alpha (eEF1A) in complex with GTP delivers an aminoacylated tRNA to the A site of the ribosome. Following the proper codon-anticodon recognition the GTP is hydrolyzed and the inactive eEF1A-GDP is released from the ribosome and then it is bound by eEF1B2GD complex forming the macromolecular protein aggregate eEF1H. eEF1H is formed previously by the binding of three subunits: eEF1B2, eEF1G and eEF1D. This complex promotes the exchange between GDP and GTP to regenerate active form of eEF1A (reworked from Dongsheng et al., 2013; Ejiri, 2002; Riis et al, 1990; https://reactome.org) Expression Localisation eEF1D is expressed widely in human tissues and eEF1D is located mostly in the cytoplasm but it is high levels of protein are reported in bone marrow also found in the nucleus, especially its long form stromal cells (https://www.genecards.org). The long (Kaitsuka et al., 2011), and also in relation with the form of eEF1D (eEF1DL) is found to be highly endoplasmic reticulum (Sanders et al., 1996). expressed in brain and testis (Kaitsuka et al., 2011).

Figure 4. Subcellular localization of eEF1D. Cytoplasmic and nuclear localizations for eEF1D were determined by transfection experiments with GFP-eEF1D fusion proteins for both isoforms (GFP-eEF1D and GFP-eEF1DL) in HeLa cells. The tests were made by confocal microscopy with a scale bar of 20 m. eEF1D was found also in relation to the endoplasmic reticulum (ER) in primary fibroblasts VH25 cells. The long form of EEF1D (EF1DL) is the only isoform that is found also in nucleus, while in the cytoplasm and on ER co-localize both long and short isoforms (reworked from Kaitsuka et al., 2011; Sanders et al., 1996. Note: some picture elements were obtained from using BioRender illustration tool).

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EEF1D (eukaryotic translation elongation factor 1 delta) Cristiano L

Mosquito AgaP_AGA Function A.gambiae 48.5 57.0 (Anopheles) P004235 eEF1D has shown to cover an important role in Caenorhabdi normal brain functioning and development and some C.elegans eef-1B.2 53.8 57.6 tis experiments on KO mice lacking the expression of Table.3 EEF1D homology (reworked from its long isoform (eEF1DL) have done emerging its ps://www.ncbi.nlm.nih.gov/homologene) implication for normal physiology of the brain. In fact, in these KO mice were observed severe seizures Mutations in response to loud sounds and also significant brain structure alterations such as a decrease in brain Note weight, atrophy of the hippocampus and midbrain A great number of mutations in the genomic and a reduction of cortical layer thickness (Kaitsuka sequence and in the amino acid sequence for EEF1D et al., 2018). were discovered in cancer cells that are obviously eEF1D shows canonical functions and multiple non- genetically more unstable respect normal ones. The canonical roles (moonlighting roles) inside the cell. genomic alterations observed include the formation Canonical function: eEF1D binds to eEF1B and of novel fusion genes. However, there are no eEF1G in the eEF1BDG macromolecular complex sufficient experimental data yet to understand the and contributes to catalyze the exchange of repercussions on cellular behaviour and so the GDP/GTP for eEF1A during the translation implications in cancer of these fusion genes. elongation cycle. Non-canonical roles: eEF1D seems to have other functions inside the cell besides its involvement in translation. At least two other non-canonical roles have been detected, i.e. its role as a transcriptional factor and its involvement in the stress response. These roles are closely connected to each other. In fact, it was demonstrated that heat shock induces the splicing-dependent expression change from the short eEF1D isoform (isoform 2) to the eEF1DL long isoform (isoform 1)(Kaitsuka et al., 2015). The silencing of eEF1DL inhibits the stress responses suggesting its role in the modulation of stress response in the cell (Hensen et al., 2013). In fact, EEF1D is a heat shock transcription factor that can bind to the heat shock element (HSE) in the promoter of the HSPA6 and HO-1 genes and activate their transcription (Kaitsuka et al., 2011). Homology Figure 5. Circos plot for fusion events involving eEF1D. eEF1D is highly conserved and its homology The picture summarizes all fusion events concerning between the species is reported in Table.3 eEF1D and its fusion partners (from https://fusionhub.persistent.co.in/search_genewise.html). DNA PROT Organism Species Symbol Identity Identity (%) (%) Implicated in Human H.sapiens EEF1D 100 100 Top note Chimpanzee P.troglodytes EEF1D 99.6 99.3 EEF1D is a cellular proto-oncogene (Joseph et al., Macaco M.mulatta EEF1D 95.7 95.7 2002) and it is involved in many and heterogeneous Wolf C.lupus LOC475115 85.2 85.5 genomic translocations in different kind of tumors Cattle B.taurus EEF1D 92.1 88.3 with also the creation of numerous fusion gene (Table.4). An increase of its expression level has an Mouse M.musculus Eef1d 85.2 84.3 oncogenic potential with resulting in cell Rat R.norvegicus Eef1d 86.8 84.5 transformation (Lei et al., 2002) and this was Chicken G.gallus EEF1D 57.7 61.6 observed in many cancer types (Hassan et al., 2018). Xenopus In addition, the use of antisense mRNA to block X.tropicalis eef1d 67.8 69.7 tropicalis EEF1D translation can revert its oncogenic potential Zebrafish D.rerio eef1db 65.8 66.3 (Lei et al., 2002). These data could suggest its role D.melanogas as a potential diagnostic indicator and prognostic Fruit fly eEF1delta 55.6 57.0 ter marker in tumors (Joseph et al., 2002).

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EEF1D (eukaryotic translation elongation factor 1 delta) Cristiano L

Name 5' end 3' end Loc1 Loc2 Description Type Disease Organ Code Ref. ACSF2/EEF1D ACSF2 EEF1D 17q21.33 8q24.3 t(8;17)(q24;q21) Translocation (?) - - - AGO2/EEF1D AGO2 EEF1D 8q24.3 8q24.3 t(8;8)(q24;q24) Fusion gene (?) - - - ASAP1/EEF1D ASAP1 EEF1D 8q24.21 8q24.3 t(8;8)(q24;q24) Fusion gene (?) - - - ASB8/EEF1D ASB8 EEF1D 12q13.11 8q24.3 t(8;12)(q24;q13) Translocation (?) - - - ATXN1/EEF1D ATXN1 EEF1D 6p22.3 8q24.3 t(6;8)(p22;q24) Translocation (?) - - - B2M/EEF1D B2M EEF1D 15q21.1 8q24.3 t(8;15)(q24;q21) Translocation (?) - - - BOD1L1/EEF1D BOD1L1 EEF1D 4p15.33 8q24.3 t(4;8)(p15;q24) Translocation (?) - - - C19ORF10/EEF1D C19ORF10 EEF1D 19p13.3 8q24.3 t(8;19)(q24;p13) Translocation (?) - - - CAPN15/EEF1D CAPN15 EEF1D 16p13.3 8q24.3 t(8;16)(q24;p13) Translocation (?) - - - CBX7/EEF1D CBX7 EEF1D 22q13.1 8q24.3 t(8;22)(q24;q13) Translocation (?) - - - CHN2/EEF1D CHN2 EEF1D 7p14.3 8q24.3 t(7;8)(p14;q24) Translocation (?) - - - CLPS/EEF1D CLPS EEF1D 6p21.31 8q24.3 t(6;8)(p21;q24) Translocation (?) - - - CLTB/EEF1D CLTB EEF1D 5q35.2 8q24.3 t(5;8)(q35;q24) Translocation (?) - - - CMSS1/EEF1D CMSS1 EEF1D 3q12.1 8q24.3 t(3;8)(q12;q24) Translocation (?) - - - COLGALT1/EEF1D COLGALT1 EEF1D 19p13.11 8q24.3 t(8;19)(q24;p13) Translocation (?) - - - CRY1/EEF1D CRY1 EEF1D 12q23.3 8q24.3 t(8;12)(q24;q23) Translocation (?) - - - CTDP1/EEF1D CTDP1 EEF1D 18q23 8q24.3 t(8;18)(q24;q23) Translocation (?) - - - CTTN/EEF1D CTTN EEF1D 11q13.3 8q24.3 t(8;11)(q24;q13) Translocation (?) - - - DDX23/EEF1D DDX23 EEF1D 12q13.12 8q24.3 t(8;12)(q24;q13) Translocation (?) - - - DDX5/EEF1D DDX5 EEF1D 17q23.3 8q24.3 t(8;17)(q24;q23) Translocation (?) - - - ANKRD Adenoca EEF1D/ANKRD19P EEF1D 8q24.3 9q22.31 t(8;9)(q24;q22) Translocation Stomach STAD - 19P rcinoma Babice 19p13. MCF1 anu et EEF1D/CALR EEF1D CALR 8q24.3 t(8;19)(q24;p13) Translocation - Cell line 13 0 al.,201 6 14q32. EEF1D/CKB EEF1D CKB 8q24.3 t(8;14)(q24;q32) Translocation (?) - - - 33 EEF1D/DUSP28 EEF1D DUSP28 8q24.3 2q37.3 t(2;8)(q37;q24) Translocation (?) - - - EEF1DP 19p13.1 EEF1D/EEF1DP1 EEF1D 8q24.3 t(8;19)(q24;p13) Translocation (?) - - - 1 2 EEF1DP EEF1D/EEF1DP5 EEF1D 8q24.3 6q22.33 t(6;8)(q22;q24) Translocation (?) - - - 5 EEF1D/GSDMB EEF1D GSDMB 8q24.3 17q12 t(8;17)(q24;q12) Translocation (?) - - - Babice 12q13. Esophag anu et EEF1D/KRT4 EEF1D KRT4 8q24.3 t(8;12)(q24;q13) Translocation - - 13 us al.,201 6 Squamou Klijn 12q13. s Cell Head and EEF1D/KRT5 EEF1D KRT5 8q24.3 t(8;12)(q24;q13) Translocation HNSC et al., 13 Carcino Neck 2015 ma Squamou Klijn 12q13. s Cell Head and EEF1D/KRT6A EEF1D KRT6A 8q24.3 t(8;12)(q24;q13) Translocation HNSC et al., 13 Carcino Neck 2015 ma Babice 17q21. anu et EEF1D/KRT10 EEF1D KRT10 8q24.3 t(8;17)(q24;q21) Translocation - Skin - 2 al.,201 6 Alaei- Squamou Mahab 17q21. s Cell Uterine EEF1D/KRT14 EEF1D KRT14 8q24.3 t(8;17)(q24;q21) Translocation CESC adi et 2 Carcino cervix al., ma 2016

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EEF1D (eukaryotic translation elongation factor 1 delta) Cristiano L

11p15. EEF1D/LSP1 EEF1D LSP1 8q24.3 t(8;11)(q24;p15) Translocation (?) - - - 5 MAN2C 15q24. EEF1D/MAN2C1 EEF1D 8q24.3 t(8;15)(q24;q24) Translocation (?) - - - 1 2 ESC Babice anu et - Cell line MCF1 al.,201 0 6 Burkitt lymphom Blood BL - Readthrough a EEF1D/NAPRT EEF1D NAPRT 8q24.3 8q24.3 Fusion gene transcription Hepatoce llular Liver LIHC - carcinom a Tao et Laryngea Head and HNSC al., l cancer Neck 2018 NFKBI EEF1D/NFKBIB EEF1D 8q24.3 19q13.2 t(8;19)(q24;q13) Translocation (?) - - - B EEF1D/PARK2 EEF1D PARK2 8q24.3 6q26 t(6;8)(q26;q24) Translocation (?) - - - 10q25. EEF1D/PNLIP EEF1D PNLIP 8q24.3 t(8;10)(q24;q25) Translocation (?) - - - 3 Serous Cystaden EEF1D/PUF60 EEF1D PUF60 8q24.3 8q24.3 t(8;8)(q24;q24) Fusion gene Ovary OVSC - ocarcino ma EEF1D/RNF2 EEF1D RNF2 8q24.3 1q25.3 t(1;8)(q25;q24) Translocation (?) - - - 19q13. EEF1D/RYR1 EEF1D RYR1 8q24.3 t(8;19)(q24;q13) Translocation (?) - - - 2 Wu et 20q13. Adenoca EEF1D/SDC4 EEF1D SDC4 8q24.3 t(8;20)(q24;q13) Translocation Prostate PRAD al., 12 rcinoma 2012 EEF1D/SFTPC EEF1D SFTPC 8q24.3 8p21.3 t(8;8)(q24;p21) Fusion gene (?) - - - Burkitt 19q13. EEF1D/SPIB EEF1D SPIB 8q24.3 t(8;19)(q24;q13) Translocation lymphom Blood BL - 33 a Thyroid EEF1D/TG EEF1D TG 8q24.3 8q24.22 t(8;8)(q24;q24) Fusion gene carcinom Thyroid THCA - a Serous TSNAR Cystaden EEF1D/TSNARE1 EEF1D 8q24.3 8q24.3 t(8;8)(q24;q24) Fusion gene Ovary OVSC - E1 ocarcino ma Yoshi Adenoca hara et EEF1D/TSTA3 EEF1D TSTA3 8q24.3 8q24.3 t(8;8)(q24;q24) Fusion gene Lung LUAD rcinoma al 2015 UBE2L 22q11.2 EEF1D/UBE2L3 EEF1D 8q24.3 t(8;22)(q24;q11) Translocation (?) - - - 3 1 ZBTB7 19p13. EEF1D/ZBTB7A EEF1D 8q24.3 t(8;19)(q24;p13) Translocation (?) - - - A 3 EEF1D/ZC3H3 EEF1D ZC3H3 8q24.3 8q24.3 t(8;8)(q24;q24) Fusion gene (?) - - - Klijn COLO FAM104A/EEF1D FAM104A EEF1D 17q25.1 8q24.3 t(8;17)(q24;q25) Translocation - Cell line et al., 794 2015 FAM222B/EEF1D FAM222B EEF1D 17q11.2 8q24.3 t(8;17)(q24;q11) Translocation (?) - - - FLCN/EEF1D FLCN EEF1D 17p11.2 8q24.3 t(8;17)(q24;p11) Translocation (?) - - - Burkitt HDAC5/EEF1D HDAC5 EEF1D 17q21.31 8q24.3 t(8;17)(q24;q21) Translocation lymphom Blood BL - a

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EEF1D (eukaryotic translation elongation factor 1 delta) Cristiano L

Klijn OVTO HIF1A/EEF1D HIF1A EEF1D 14q23.2 8q24.3 t(8;14)(q24;q23) Translocation - Cell line et al., KO 2015 HIF3A/EEF1D HIF3A EEF1D 19q13.32 8q24.3 t(8;19)(q24;q13) Translocation (?) - - - HRH1/EEF1D HRH1 EEF1D 3p25.3 8q24.3 t(3;8)(p25;q24) Translocation (?) - - - MOLP - Cell line -8 Klijn IGLL5/EEF1D IGLL5 EEF1D 22q11.22 8q24.3 t(8;22)(q24;q11) Translocation et al., Adenoca Stomach STAD 2015 rcinoma IL4R/EEF1D IL4R EEF1D 16p12.1 8q24.3 t(8;16)(q24;p12) Translocation (?) - - - IRF3/EEF1D IRF3 EEF1D 19q13.33 8q24.3 t(8;19)(q24;q13) Translocation (?) - - - Babice Esophag anu et KRT13/EEF1D KRT13 EEF1D 17q21.2 8q24.3 t(8;17)(q24;q21) Translocation - - us al.,201 6 LGR6/EEF1D LGR6 EEF1D 1q32.1 8q24.3 t(1;8)(q32;q24) Translocation (?) - - - METRNL/EEF1D METRNL EEF1D 17q25.3 8q24.3 t(8;17)(q24;q25) Translocation (?) - - - MGRN1/EEF1D MGRN1 EEF1D 16p13.3 8q24.3 t(8;16)(q24;p13) Translocation (?) - - - NCAM1/EEF1D NCAM1 EEF1D 11q23.2 8q24.3 t(8;11)(q24;q23) Translocation (?) - - - NID1/EEF1D NID1 EEF1D 1q42.3 8q24.3 t(1;8)(q42;q24) Translocation (?) - - - OAZ1/EEF1D OAZ1 EEF1D 19p13.3 8q24.3 t(8;19)(q24;p13) Translocation (?) - - - Klijn ES2- OGG1/EEF1D OGG1 EEF1D 3p25.3 8q24.3 t(3;8)(p25;q24) Translocation - Cell line et al., TO 2015 Adenoca OPLAH/EEF1D OPLAH EEF1D 8q24.3 8q24.3 t(8;8)(q24;q24) Fusion gene Stomach STAD - rcinoma Adenoca PLA2G6/EEF1D PLA2G6 EEF1D 22q13.1 8q24.3 t(8;22)(q24;q13) Translocation Breast BRCA - rcinoma PLIN5/EEF1D PLIN5 EEF1D 19p13.3 8q24.3 t(8;19)(q24;p13) Translocation (?) - - - Klijn PMF1/EEF1D PMF1 EEF1D 1q22 8q24.3 t(1;8)(q22;q24) Translocation - Cell line RT4 et al., 2015 POLI/EEF1D POLI EEF1D 18q21.2 8q24.3 t(8;18)(q24;q21) Translocation (?) - - - POU2F1/EEF1D POU2F1 EEF1D 1q24.2 8q24.3 t(1;8)(q24;q24) Translocation (?) - - - PSMB7/EEF1D PSMB7 EEF1D 9q33.3 8q24.3 t(8;9)(q24;q33) Translocation (?) - - - PTP4A3/EEF1D PTP4A3 EEF1D 8q24.3 8q24.3 t(8;8)(q24;q24) Fusion gene (?) - - - RAB3GAP1/EEF1D RAB3GAP1 EEF1D 2q21.3 8q24.3 t(2;8)(q21;q24) Translocation (?) - - - RAB40C/EEF1D RAB40C EEF1D 16p13.3 8q24.3 t(8;16)(q24;p13) Translocation (?) - - - RCC1/EEF1D RCC1 EEF1D 1p35.3 8q24.3 t(1;8)(p35;q24) Translocation (?) - - - RILPL2/EEF1D RILPL2 EEF1D 12q24.31 8q24.3 t(8;12)(q24;q24) Translocation (?) - - - RNF14/EEF1D RNF14 EEF1D 5q31.3 8q24.3 t(5;8)(q31;q24) Translocation (?) - - - RNF44/EEF1D RNF44 EEF1D 5q35.2 8q24.3 t(5;8)(q35;q24) Translocation (?) - - - Adenoca RPL30 /EEF1D RPL30 EEF1D 8q22.2 8q24.3 t(8;8)(q22;q24) Fusion gene Breast BRCA - rcinoma RPL36AL/EEF1D RPL36AL EEF1D 14q21.3 8q24.3 t(8;14)(q24;q21) Fusion gene (?) - - - Burkitt RPS9/EEF1D RPS9 EEF1D 19q13.42 8q24.3 t(8;19)(q24;q13) Translocation lymphom Blood BL - a RSAD1/EEF1D RSAD1 EEF1D 17q21.33 8q24.3 t(8;17)(q24;q21) Translocation (?) - - - Serous Cystaden SCRIB/EEF1D SCRIB EEF1D 8q24.3 8q24.3 t(8;8)(q24;q24) Fusion gene Ovary OVSC - ocarcino ma SCYL1/EEF1D SCYL1 EEF1D 11q13.1 8q24.3 t(8;11)(q24;q13) Translocation (?) - - -

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EEF1D (eukaryotic translation elongation factor 1 delta) Cristiano L

Burkitt SH2B2/EEF1D SH2B2 EEF1D 7q22.1 8q24.3 t(7;8)(q22;q24) Translocation lymphom Blood BL - a SMYD3/EEF1D SMYD3 EEF1D 1q44 8q24.3 t(1;8)(q44;q24) Translocation (?) - - - SORBS1/EEF1D SORBS1 EEF1D 10q24.1 8q24.3 t(8;10)(q24;q24) Translocation (?) - - - SORT1 /EEF1D SORT1 EEF1D 1p13.3 8q24.3 t(1;8)(p13;q24) Translocation (?) - - - Burkitt SPIB/EEF1D SPIB EEF1D 19q13.33 8q24.3 t(8;19)(q24;q13) Translocation lymphom Blood BL - a ST3GAL1/EEF1D ST3GAL1 EEF1D 8q24.22 8q24.3 t(8;8)(q24;q24) Fusion gene (?) - - - Adenoca TATDN1/EEF1D TATDN1 EEF1D 8q24.13 8q24.3 t(8;8)(q24;q24) Fusion gene Breast BRCA - rcinoma TMEM99/EEF1D TMEM99 EEF1D 17q21.2 8q24.3 t(8;17)(q24;q21) Translocation (?) - - - TMLHE/EEF1D TMLHE EEF1D Xq28 8q24.3 t(X;8)(q28;q24) Translocation (?) - - - TOP2B/EEF1D TOP2B EEF1D 3p24.2 8q24.3 t(3;8)(p24;q24) Translocation (?) - - - TP53I3/EEF1D TP53I3 EEF1D 2p23.3 8q24.3 t(2;8)(p23;q24) Translocation (?) - - - TP53TG5/EEF1D TP53TG5 EEF1D 20q13.12 8q24.3 t(8;20)(q24;q13) Translocation (?) - - - TTC21B/EEF1D TTC21B EEF1D 2q24.3 8q24.3 t(2;8)(q24;q24) Translocation (?) - - - Carcino Esophag TTLL3/EEF1D TTLL3 EEF1D 3p25.3 8q24.3 t(3;8)(p25;q24) Translocation ESCA - ma us UBAP2/EEF1D UBAP2 EEF1D 9p13.3 8q24.3 t(8;9)(q24;p13) Translocation (?) - - - UBE2G1/EEF1D UBE2G1 EEF1D 17p13.2 8q24.3 t(8;17)(q24;p13) Translocation (?) - - - Adenoca UFM1/EEF1D UFM1 EEF1D 13q13.3 8q24.3 t(8;13)(q24;q13) Translocation Colon COAD - rcinoma XRN2/EEF1D XRN2 EEF1D 20p11.23 8q24.3 t(8;20)(q24;p11) Translocation (?) - - - Babice Bone anu et - marrow al.,201 - 6 ZC3H3/EEF1D ZC3H3 EEF1D 8q24.3 8q24.3 t(8;8)(q24;q24) Fusion gene Klijn Cell line Ca Ski et al., 2015 Carcino Esophag ESCA - ma us ZG16B/EEF1D ZG16B EEF1D 16p13.3 8q24.3 t(8;16)(q24;p13) Translocation (?) - - - ZNF146/EEF1D ZNF146 EEF1D 19q13.12 8q24.3 t(8;19)(q24;q13) Translocation (?) - - - ZNF232/EEF1D ZNF232 EEF1D 17p13.2 8q24.3 t(8;17)(q24;p13) Translocation (?) - - - ZNF429/EEF1D ZNF429 EEF1D 19p12 8q24.3 t(8;19)(q24;p12) Translocation (?) - - - ZNF608/EEF1D ZNF608 EEF1D 5q23.2 8q24.3 t(5;8)(q23;q24) Translocation (?) - - - Table.4 EEF1D rearrangements: translocations and fusion genes (reworked from ps://www.ncbi.nlm.nih.gov/homologene; http://www.tumorfusions.org; https://cgap.nci.nih.gov/Chromosomes; http://quiver.archerdx.com; http://atlasgeneticsoncology.org//Bands/8q24.html#REFERENCES; https://fusionhub.persistent.co.in/home.html; https://ccsm.uth.edu/FusionGDB/index.html) [ (?) ] unknown; [ - ] no reference Amyotrophic lateral sclerosis (ALS) (Klijn et al., 2015). This rearrangement is originated by the fusion of "polyamine modulated factor 1" EEF1D is a potential candidate gene associated with (PMF1) gene at 5'-end with EEF1D gene at 3' end. ALS (Wain et al., 2009) but more studies are needed There are no data about its chimeric transcript or to clarify its effective contribution. protein and the role of this genomic alteration is Bladder cancer poorly understood. There are no data about EEF1D expression Brain and central nervous system alterations in bladder cancer. However, it was (CNS) cancers reported the translocation t(1;8)(q22;q24) PMF1/EEF1D (Klijn et al., 2015). EEF1D is found to be overexpressed in astrocytoma and in glioblastoma samples and also in low-risk Hybrid/Mutated gene patients. This may associate its expression to The t(1;8)(q22;q24) PMF1/EEF1D was detected in favourable survival outcome (Hassan et al., 2018). bladder transitional-cell carcinoma RT4 cell line

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EEF1D (eukaryotic translation elongation factor 1 delta) Cristiano L

Breast cancer on the cell of these phosphorylations as also if these changes may affect the level or speed of protein EEF1D is involved in breast cancer (Jurca et al., synthesis (Pitti et al., 2008). 2016). In fact, was detected an EEF1D gene copy number gain in BT483, EFM19, HCC1143, Colorectal cancer HCC1395, HCC1569, HCC1806, HCC1937, It was detected an EEF1D gene copy number gain in HCC2157, HCC2218, HDQP1, MDAMB436 and LS123 and RKO colorectal cancer cell lines and in UACC893 breast cancer cell lines and in about 10% about 5% of colon adenocarcinoma donor samples of breast invasive carcinoma donor samples (http://www.oasis-genomics.org/). In addition, (http://www.oasis-genomics.org/). EEF1D was EEF1D transcript is found to be significantly found overexpressed in T-47, MCF-7, MDA-MB- overexpressed (Hassan et al., 2018), especially in the 361 and MDA-MB-453 breast cancer cell lines right-sided colon cancer (RSCC) respect left-sided (Joseph et al., 2004). It is also overexpressed in colon cancer (LSCC) samples (Shen et al., 2013). It breast cancer samples and this predicted worse was reported the translocation t(8;13)(q24;q13) relapse-free survival (RFS) in luminal A subtype UFM1/EEF1D patients and poor overall survival (OS) and RFS in (https://fusionhub.persistent.co.in/home.html). basal subtype (Hassan et al., 2018). Hybrid/Mutated gene Some authors have found an EEF1D downregulation in ER+/ER- cancer cell lines and in human breast The t(8;13)(q24;q13) UFM1/EEF1D was found in cancer samples when high levels of bone colon adenocarcinoma. This rearrangement is morphogenetic protein-6 ( BMP6) are expressed originated by the fusion of 'ubiquitin fold modifier 1' (Yang et al., 2007). This seems to be linked with the ( UFM1) gene at 5'-end with EEF1D gene at 3' end. prevention of eEF1D-induced breast cancer There are no data about the respective chimeric metastasis. In fact, EEF1D is a candidate protein transcript or protein and the role of this genomic marker of human brain metastasis in primary breast alteration is unknown. tumors (Sanz-Pamplona et al., 2011; van't Veer et al., Gastric cancer 2002). In addition, some fusion genes and genomic It was detected an EEF1D gene copy number gain in translocations were reported 2313287, LMSU, MKN1, SNU5, SNU216, SNU601 (https://fusionhub.persistent.co.in/home.html). and SNU668 gastric cancer cell lines Hybrid/Mutated gene (http://www.oasis-genomics.org/) but it was found The translocation t(8;22)(q24;q13) PLA2G6/EEF1D down-expressed in gastric cancer samples (Hassan et was found in breast carcinoma (BRCA) and consists al., 2018). Some fusion genes and genomic by the fusion of 'phospholipase A2 group VI' (< CC: translocation are reported (Klijn et al., 2015; TXT: PLA2G6 ID: 45836>) gene at 5'-end with https://fusionhub.persistent.co.in/home.html). EEF1D gene at 3' end. In addition, other Hybrid/Mutated gene uncharacterized and rare rearrangements due to the The t(8;22)(q24;q11) IGLL5/EEF1D was found in translocation t(8;8)(q24;q24) are reported, i.e. the gastric adenocarcinoma samples (Klijn et al., 2015) RPL30 /EEF1D and TATDN1/EEF1D fusion genes and consists by the fusion of 'immunoglobulin (https://fusionhub.persistent.co.in/home.html). In lambda-like polypeptide 5' ( IGLL5) gene at 5'-end particular, the t(8;8)(q24;q24) RPL30 /EEF1D with EEF1D gene at 3' end. In addition, other brings to the formation of a transcript composed by uncharacterized and rare rearrangements are the exons 1 to 3 of RPL30 joined with exons 2 to 7 reported, i.e. OPLAH/EEF1D fusion gene and of EEF1D t(8;9)(q24;q22) EEF1D/ANKRD19P (http://203.255.191.229:8080/chimerdbv31/chimers (https://fusionhub.persistent.co.in/home.html). In eq_link.cdb?gene_pair=RPL30_EEF1D), while the particular, the t(8;9)(q24;q22) EEF1D/ANKRD19P t(8;8)(q24;q24) TATDN1/EEF1D brings to the brings to the formation of a new chimeric gene with formation of a transcript composed by the exon 1 of a transcript formed by the exons 1 to 5 of EEF1D TATDN1 joined with exons 2 to 7 of EEF1D joined with exon 10 of 'ankyrin repeat domain 19 (http://203.255.191.229:8080/chimerdbv31/chimers pseudogene' ( ANKRD19P). The protein resulting eq_link.cdb?gene_pair=TATDN1_EEF1D). from this rearrangement lacks the GEF domain in the Despite what has just been said, these genomic C-terminal alterations are still poorly understood. (http://203.255.191.229:8080/chimerdbv31/chimers Chondrosarcoma eq_link.cdb?gene_pair=EEF1D_ANKRD19P). The human chondrosarcoma cells are able to respond Despite what has just been said, these genomic to mechanical stimuli, like cellular stretching, with alterations are still poorly understood. different phosphorylation events. Increase of phosphorylations impacts also on the EEF1D protein. It is unclearly the significance or the effect

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EEF1D (eukaryotic translation elongation factor 1 delta) Cristiano L

Head and neck squamous cell rearrangement is originated by the fusion of EEF1D carcinoma (HNSC) gene at 5'-end with 'nicotinate phosphoribosyltransferase domain containing 1' EEF1D gene was found up-regulated in head and (NAPRT) gene at 3' end and it is probably due to neck squamous cell carcinoma (HNSC) (Hassan et readthrough transcription. In fact, EEF1D and al., 2018; Han et al., 2009). In particular, Flores and NAPRT1 are two neighboring genes on the same colleagues (Flores et al., 2016) detected its chromosome. There are no data about the respective overexpression in oral squamous cell carcinoma chimeric transcript or protein and the role of this (OSCC) respect to oral healthy mucosa. It could genomic alteration is unknown. have a critical role both in cell proliferation and in Lung cancer epithelial-mesenchymal transition (EMT). In fact, EEF1D knockdown shown a decrease in cell cycle EEF1D was found to be down-expressed in lung rate and proliferation. Some fusion genes and carcinoid tumor and not shows any correlation with genomic translocation are reported (Klijn et al., survival parameters (Hassan et al., 2018). 2015). It was also found down-expressed in adriamycin- In addition, EEF1D was found up-regulated in resistant variants of DLKP squamous lung cancer human laryngeal cancer (Peyvandi et al., 2018) and cell line (Keenan et al., 2009). On the contrary, other was found an intrachromosomal translocation with authors found overexpression of EEF1D mRNA in the formation of a chimeric fusion gene between some adenocarcinoma of the lung and squamous EEF1D and NAPRT1 genes in laryngeal cancer (Tao lung cell carcinoma tissue samples (Varemieva et al., et al., 2018). 2014). In addition, eEF1D was found both in the cytoplasm and in the nucleus of lung Hybrid/Mutated gene adenocarcinoma A549 cell line (Varemieva et al., The t(8;12)(q24;q13) EEF1D/KRT5 and the 2014) and the EEF1D/TSTA3 fusion gene was t(8;12)(q24;q13) EEF1D/KRT6A were found in reported for lung adenocarcinoma head and neck squamous cell carcinoma (HNSC) (LUAD)(Yoshihara et al 2015). samples with the production of chimeric genes originated by the fusion of EEF1D at 5'-end with Hybrid/Mutated gene 'keratin 5' ( KRT5) or 'keratin 6A' ( KRT6A) genes The EEF1D/TSTA3 fusion gene was found in lung at 3' end (Klijn et al., 2015). In addition, it was adenocarcinoma (LUAD) samples (Yoshihara et al detected in laryngeal cancer the fusion gene 5' 2015). This rearrangement is originated by EEF1D - 3' NAPRT (Tao et al., 2018) that is t(8;8)(q24;q24) i.e. from the fusion of EEF1D gene probably originated by readthrough transcription, a at 5'-end with 'tissue specific transplantation antigen known mechanism into the cell (He et al., 2018). In P35B' ( TSTA3) gene at 3' end. In particular, this fact, EEF1D and NAPRT1 are two neighboring rearrangement brings to the formation of a transcript genes on the same chromosome. composed by the exon 1 of EEF1D joined with exons The roles of all these genomic alterations are 4 to 11 of TSTA3 unknown. (http://203.255.191.229:8080/chimerdbv31/chimers eq_link.cdb?gene_pair=EEF1D_TSTA3). Despite Kidney cancer what has just been said, this genomic alteration is High EEF1D mRNA levels were found in renal still poorly understood. Wilms tumor and in clear cell carcinoma (Hassan et Lymphoma and other blood cancers al., 2018). Some authors have detected missense mutations of EEF1D in papillary renal cell EEF1D is significantly overexpressed in different carcinoma (PRCC)(Liu et al., 2015). These lymphoma subtypes, i.e. ALK-negative/ ALK mutations could contribute to the pathogenic positive anaplastic large cell lymphomas, Hodgkin's mechanism for PRCC but more studies are lymphoma, acute adult T-cell leukaemia/lymphoma, necessary. Burkitt's lymphoma, follicular lymphoma and diffuse large B-cell lymphoma (Hassan et al., 2018). Liver cancer Some fusion genes and genomic translocation were EEF1D was found overexpressed in moderately to reported (Klijn et al., 2015; poorly differentiated (M/P-) primary human https://fusionhub.persistent.co.in/home.html; hepatocellular carcinoma (HCC) tissues (Hassan et https://ccsm.uth.edu/FusionGDB/index.html). al., 2018; Shuda et al., 2000). In addition, it was Cytogenetics found the EEF1D/NAPRT fusion gene The t(8;19)(q24;q13) EEF1D/ SPIB, (https://fusionhub.persistent.co.in/home.html; t(8;17)(q24;q21) HDAC5/EEF1D, t(8;19)(q24;q13) https://ccsm.uth.edu/FusionGDB/index.html). RPS9/EEF1D, t(7;8)(q22;q24) SH2B2/EEF1D, Hybrid/Mutated gene t(8;19)(q24;q13) SPIB/EEF1D translocations and The EEF1D/NAPRT fusion gene was found in EEF1D/NAPRT fusion gene were reported for hepatocellular carcinoma (LIHC). This Burkitt's lymphoma (BL). In addition, the

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t(8;22)(q24;q11) IGLL5/EEF1D was observed in metastasis and this correlates with poor prognosis multiple myeloma MOLP-8 cell line (Klijn et al., (Ogawa et al., 2004). 2015). Some fusion genes and genomic translocation are There are no data about the respective chimeric reported (Babiceanu et al.,2016; transcripts or proteins and the role of these genomic https://fusionhub.persistent.co.in/home.html; alterations is unknown. https://ccsm.uth.edu/FusionGDB/index.html). Medulloblastoma / Ependymoma Hybrid/Mutated gene EEF1D is overexpressed in medulloblastoma The t(3;8)(p25;q24) TTLL3/EEF1D, samples and it is adversely associated with overall t(8;17)(q24;q21) KRT13/EEF1D, t(8;12)(q24;q13) and progression-free survival regardless of EEF1D/KRT4 translocations and ZC3H3/EEF1D cytogenetic profile (De Bortoli et al., 2006). fusion gene were reported in oesophageal carcinoma In addition, EEF1D was found highly expressed in (ESCA). ependymoma and this is related to poor outcome (de In particular, the t(3;8)(p25;q24) TTLL3/EEF1D Bont et al., 2008). brings to the formation of a transcript composed by the exons 1 to 3 of "tubulin tyrosine ligase like 3" ( Melanoma TTLL3) joined with exons 2 to 7 of EEF1D EEF1D was found overexpressed in human (http://203.255.191.229:8080/chimerdbv31/chimers chemoresistant melanoma cell lines (Sinha et al., eq_link.cdb?gene_pair=TTLL3_EEF1D), while the 2000) and it was reported the translocation t(8;8)(q24;q24) ZC3H3/EEF1D brings to the t(8;17)(q24;q25) FAM104A/EEF1D (Klijn et al., formation of a transcript composed by the exon 1 of 2015). "zinc finger CCCH-type containing 3" ( ZC3H3) Hybrid/Mutated gene joined with exons 4 to 7 of EEF1D (http://203.255.191.229:8080/chimerdbv31/chimers The t(8;17)(q24;q25) FAM104A/EEF1D was eq_link.cdb?gene_pair=ZC3H3_EEF1D). Despite reported in COLO794 cell line (Klijn et al., 2015). what has just been said, these genomic alterations are This rearrangement is originated by the fusion of still poorly understood. "family with sequence similarity 104 member A" ( FAM104A) gene at 5'-end with EEF1D gene at 3' Osteosarcoma end. EEF1D may play an important role in osteosarcoma There are no data about the respective chimeric tumorigenesis because it is overexpressed in transcript or protein and the role of this genomic osteosarcoma tissues samples respect to adjacent alteration is unknown. non-tumor tissues and this enhances the Akt-mTOR Neurological and and Akt-Bad signalling pathways. In fact, neurodevelopmental disorders knockdown of EEF1D in MNNG/HOS and U2OS cells (both osteosarcoma cell lines) shows a slight Mutations of EEF1D are involved in decrease in the phosphorylation of Akt, MTOR and neurodevelopmental abnormalities, severe BAD. In addition, the high expression of EEF1D has intellectual disability (ID) and microcephaly a positive correlation with recurrences and its (McLachlan et al., 2018; Reuter et al., 2017). In expression levels are higher in patients in advanced particular, some authors identified a pathogenic Enneking stage than in the early stage ones (Cheng variant of EEF1DL that could be a candidate for the et al., 2018). It was reported the translocation autosomal recessive ID (ARID) due to its loss of t(3;8)(p25;q24) OGG1/EEF1D (Klijn et al., 2015). function (Ugur Iseri et al., 2019). In addition, also the interaction between eEF1D and Hybrid/Mutated gene SIAH1 could impact on the initiation of The t(3;8)(p25;q24) OGG1/EEF1D was detected in neurodegenerative diseases when eEF1D is over- sarcoma ES2-TO cell line (Klijn et al., 2015). This expressed (Wu et al., 2011). rearrangement is originated by the fusion of "8- oxoguanine DNA glycosylase" ( OGG1) gene at 5'- Oesophageal carcinoma end with EEF1D gene at 3' end. There are no data It was detected an EEF1D gene copy number gain in about the respective chimeric transcript or protein TE8, TE10 and TE11 oesophageal cancer cell lines and so this genomic alteration is still poorly (http://www.oasis-genomics.org/) and an EEF1D understood. overexpression in oesophageal carcinoma and cardioesophageal carcinoma samples respect Ovarian cancer noncancerous ones (Veremieva et al., 2011; Ogawa It was detected an EEF1D gene copy number gain in et al., 2004). In addition, it was found a significant COV362, KURAMOCHI, OVCAR4, OVCAR8 and correlation between EEF1D overexpression and SNU119 ovarian cancer cell lines, in about 26% of advanced disease stages and also lymph node ovarian serous cystadenocarcinoma donor samples (http://www.oasis-genomics.org/) and also in

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EEF1D (eukaryotic translation elongation factor 1 delta) Cristiano L

ovarian clear cell adenocarcinomas and other translocation t(8;8)(q24;q24). There are no data ovarian cancer samples (Zhang et al., 2015; Sung et about its chimeric transcript or protein and the role al., 2013). Some fusion genes and genomic of this genomic alteration is unknown. translocation are reported (Klijn et al., 2015; Uterine cancer https://fusionhub.persistent.co.in/home.html; https://ccsm.uth.edu/FusionGDB/index.html). It was detected an EEF1D gene copy number gain in about 14% of uterine carcinosarcoma donor samples Hybrid/Mutated gene (http://www.oasis-genomics.org/). It was found the The EEF1D/ PUF60, EEF1D/ TSNARE1 and translocation t(8;17)(q24;q21) EEF1D/KRT14 SCRIB/EEF1D fusion genes originated by (Alaei-Mahabadi et al., 2016). t(8;8)(q24;q24) were found in ovarian serous cystadenocarcinoma (OVSC) samples. In addition, Hybrid/Mutated gene the t(8;14)(q24;q23) HIF1A/EEF1D was reported The t(8;17)(q24;q21) EEF1D/KRT14 was found in for ovarian clear cell adenocarcinoma OVTOKO cell cervical squamous cell carcinoma (CESC). This line (Klijn et al., 2015). This rearrangement is rearrangement is originated by the fusion of EEF1D originated by the fusion of "hypoxia inducible factor gene at 5'-end with "keratin 14" ( KRT14) gene at 3' 1 subunit alpha" ( HIF1A) gene at 5'-end with end. There are no data about the respective chimeric EEF1D gene at 3' end. The roles of these genomic transcript or protein and the role of this genomic alterations are still unknown. alteration is unknown. Pancreatic cancer To be noted EEF1D mRNA is found to be down-regulated in Role of eEF1D in viral replication and pathogenesis. pancreatic cancer tissue samples (Hassan et al., Have been discovered some interactions between 2018). some human immunodeficiency virus type 1 (HIV- Parkinson's disease 1) proteins, such as HIV-1 Tat, and eEF1D and its Some rare mutated variants of eEF1D are considered recruitment for the viral mRNAs translation (Milev potential candidates in Parkinson's disease. These et al., 2012). In addition, eEF1D can be found mutated variants differ from the amino acid hyperphosphorylated by viral protein kinases after sequence of EEF1D for some amino acids alpha-, beta-, and gammaherpesviruses infections. In substitutions, i.e. in position 290 (Gly/Arg), 325 particular, the viral protein kinases involved in (Ala/Thr), 549 (Ala/Val) and 601 (Pro/Ser) (Schulte eEF1D phosphorylation include UL13 of herpes et al., 2014). simplex virus type 1 (HSV-1), UL97 of human cytomegalovirus and BGLF4 of Epstein-Barr virus Prostate cancer (EBV) (Kawaguchi et al., 2003). Apart from that, in EEF1D mRNA is found to be up-regulated in general, this brings a reduction of cellular proteins prostate cancer tissue samples (Hassan et al., 2018). biosynthesis efficiency instead privileging the viral In addition, it was found the translocation proteins translation process (Milev et al., 2012). t(8;20)(q24;q13) EEF1D/SDC4 (Wu et al., 2012). Hybrid/Mutated gene References The t(8;20)(q24;q13) EEF1D/SDC4 was found in Alaei-Mahabadi B, Bhadury J, Karlsson JW, Nilsson JA, prostate adenocarcinoma (PRAD). This Larsson E. Global analysis of somatic structural genomic rearrangement is originated by the fusion of EEF1D alterations and their impact on gene expression in diverse human cancers. Proc Natl Acad Sci U S A. 2016 Nov gene at 5'-end with "syndecan 4" ( SDC4) gene at 3' 29;113(48):13768-13773 end. There are no data about the respective chimeric transcript or protein and the role of this genomic Babiceanu M, Qin F, Xie Z, Jia Y, Lopez K, Janus N, Facemire L, Kumar S, Pang Y, Qi Y, Lazar IM, Li H. alteration in prostate cancer is unknown. Recurrent chimeric fusion RNAs in non-cancer tissues and cells. Nucleic Acids Res. 2016 Apr 7;44(6):2859-72 Thyroid cancer Bec G, Kerjan P, Waller JP. Reconstitution in vitro of the There are no data about EEF1D expression valyl-tRNA synthetase-elongation factor (EF) 1 beta gamma alterations in thyroid cancers. However, it was delta complex. Essential roles of the NH2-terminal reported the EEF1D/TG fusion gene extension of valyl-tRNA synthetase and of the EF-1 delta subunit in complex formation. J Biol Chem. 1994 Jan (https://fusionhub.persistent.co.in/home.html; 21;269(3):2086-92 https://ccsm.uth.edu/FusionGDB/index.html). Browne GJ, Proud CG. Regulation of peptide-chain Hybrid/Mutated gene elongation in mammalian cells. Eur J Biochem. 2002 The EEF1D/TG fusion gene was reported in thyroid Nov;269(22):5360-8 Carcinoma (THCA). This rearrangement is Cao Y, Portela M, Janikiewicz J, Doig J, Abbott CM. originated by the fusion of EEF1D gene at 5'-end Characterisation of translation elongation factor eEF1B with "thyroglobulin" ( TG) gene at 3' end due to the subunit expression in mammalian cells and tissues and co-

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localisation with eEF1A2 PLoS One 2014 Dec BZ, Ong TM. Expression profile of eukaryotic translation 1;9(12):e114117 factors in human cancer tissues and cell lines Mol Carcinog 2004 Jul;40(3):171-9 Cheng DD, Li SJ, Zhu B, Zhou SM, Yang QC. EEF1D overexpression promotes osteosarcoma cell proliferation by Jurca G, Addam O, Aksac A, Gao S, Özyer T, Demetrick D, facilitating Akt-mTOR and Akt-bad signaling J Exp Clin Alhajj R. Integrating text mining, data mining, and network Cancer Res 2018 Mar 6;37(1):50 analysis for identifying genetic breast cancer trends BMC Res Notes 2016 Apr 26;9:236 De Bortoli M, Castellino RC, Lu XY, Deyo J, Sturla LM, Adesina AM, Perlaky L, Pomeroy SL, Lau CC, Man TK, Rao Kaitsuka T, Tomizawa K, Matsushita M. Transformation of PH, Kim JY. Medulloblastoma outcome is adversely eEF1Bδ into heat-shock response transcription factor by associated with overexpression of EEF1D, RPL30, and alternative splicing EMBO Rep 2011 Jul 1;12(7):673-81 RPS20 on the long arm of chromosome 8 BMC Cancer 2006 Sep 12;6:223 Kawaguchi Y, Kato K, Tanaka M, Kanamori M, Nishiyama Y, Yamanashi Y. Conserved protein kinases encoded by Erho N, Buerki C, Triche TJ, Davicioni E, Vergara IA. herpesviruses and cellular protein kinase cdc2 target the Transcriptome-wide detection of differentially expressed same phosphorylation site in eukaryotic elongation factor coding and non-coding transcripts and their clinical 1delta J Virol 2003 Feb;77(4):2359-68 significance in prostate cancer J Oncol 2012;2012:541353 Keenan J, Murphy L, Henry M, Meleady P, Clynes M. Flores IL, Kawahara R, Miguel MC, Granato DC, Proteomic analysis of multidrug-resistance mechanisms in Domingues RR, Macedo CC, Carnielli CM, Yokoo S, adriamycin-resistant variants of DLKP, a squamous lung Rodrigues PC, Monteiro BV, Oliveira CE, Salmon CR, Nociti cancer cell line Proteomics 2009 Mar;9(6):1556-66 FH Jr, Lopes MA, Santos-Silva A, Winck FV, Coletta RD, Paes Leme AF. EEF1D modulates proliferation and Kim J, Kim S, Ko S, In YH, Moon HG, Ahn SK, Kim MK, Lee epithelial-mesenchymal transition in oral squamous cell M, Hwang JH, Ju YS, Kim JI, Noh DY, Kim S, Park JH, Rhee carcinoma Clin Sci (Lond) 2016 May 1;130(10):785-99 H, Kim S, Han W. Recurrent fusion transcripts detected by whole-transcriptome sequencing of 120 primary breast Gyenis L, Duncan JS, Turowec JP, Bretner M, Litchfield cancer samples Genes Chromosomes Cancer 2015 DW. Unbiased functional proteomics strategy for protein Nov;54(11):681-91 kinase inhibitor validation and identification of bona fide protein kinase substrates: application to identification of Klijn C, Durinck S, Stawiski EW, Haverty PM, Jiang Z, Liu EEF1D as a substrate for CK2 J Proteome Res 2011 Nov H, Degenhardt J, Mayba O, Gnad F, Liu J, Pau G, Reeder 4;10(11):4887-901 J, Cao Y, Mukhyala K, Selvaraj SK, Yu M, Zynda GJ, Brauer MJ, Wu TD, Gentleman RC, Manning G, Yauch RL, Han J, Kioi M, Chu WS, Kasperbauer JL, Strome SE, Puri Bourgon R, Stokoe D, Modrusan Z, Neve RM, de Sauvage RK. Identification of potential therapeutic targets in human FJ, Settleman J, Seshagiri S, Zhang Z. A comprehensive head & neck squamous cell carcinoma Head Neck Oncol transcriptional portrait of human cancer cell lines Nat 2009 Jul 14;1:27 Biotechnol 2015 Mar;33(3):306-12 Hassan MK, Kumar D, Naik M, Dixit M. 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The role of translation Janssen GM, van Damme HT, Kriek J, Amons R, Möller W. elongation factor eEF1 subunits in neurodevelopmental The subunit structure of elongation factor 1 from Artemia disorders Hum Mutat 2019 Feb;40(2):131-141 Why two alpha-chains in this complex? J Biol Chem 1994 Dec 16;269(50):31410-7 Milev MP, Ravichandran M, Khan MF, Schriemer DC, Mouland AJ. Characterization of staufen1 Jiang S, Wolfe CL, Warrington JA, Norcum MT. Three- ribonucleoproteins by mass spectrometry and biochemical dimensional reconstruction of the valyl-tRNA analyses reveal the presence of diverse host proteins synthetase/elongation factor-1H complex and localization of associated with human immunodeficiency virus type 1 Front the delta subunit FEBS Lett 2005 Nov 7;579(27):6049-54 Microbiol 2012 Oct 25;3:367 Joseph P, Lei YX, Whong WZ, Ong TM. 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Ogawa K, Utsunomiya T, Mimori K, Tanaka Y, Tanaka F, Stefansson OA, Jonasson JG, Olafsdottir K, Bjarnason H, Inoue H, Murayama S, Mori M. Clinical significance of Th Johannsson O, Bodvarsdottir SK, Valgeirsdottir S, elongation factor-1 delta mRNA expression in oesophageal Eyfjord JE. Genomic and phenotypic analysis of BRCA2 carcinoma Br J Cancer 2004 Jul 19;91(2):282-6 mutated breast cancers reveals co-occurring changes Ong LL, Er CP, Ho A, Aung MT, Yu H. Kinectin anchors the linked to progression Breast Cancer Res 2011 Sep translation elongation factor-1 delta to the endoplasmic 29;13(5):R95 reticulum J Biol Chem 2003 Aug 22;278(34):32115-23 Sung CO, Choi CH, Ko YH, et al. Integrative analysis of Peyvandi H, Peyvandi AA, Safaei A, Zamanian Azodi M, copy number alteration and gene expression profiling in Rezaei-Tavirani M. Introducing Potential Key Proteins and ovarian clear cell adenocarcinoma Cancer Genet 2013 Pathways in Human Laryngeal Cancer: A System Biology May;206(5):145-53 Approach Iran J Pharm Res 2018 Winter;17(1):415-425 Tao Y, Gross N, Fan X, Yang J, Teng M, Li X, Li G, Zhang Piltti J, Häyrinen J, Karjalainen HM, Lammi MJ. Proteomics Y, Huang Z. Identification of novel enriched recurrent of chondrocytes with special reference to phosphorylation chimeric COL7A1-UCN2 in human laryngeal cancer changes of proteins in stretched human chondrosarcoma samples using deep sequencing BMC Cancer 2018 Mar cells Biorheology 2008;45(3-4):323-35 2;18(1):248 Reuter MS, Tawamie H, Buchert R, et al. Diagnostic Yield Ugur Iseri SA, Yucesan E, Tuncer FN, Calik M, Kesim Y, and Novel Candidate Genes by Exome Sequencing in 152 Altiokka Uzun G, Ozbek U. Biallelic loss of EEF1D function Consanguineous Families With Neurodevelopmental links heat shock response pathway to autosomal recessive Disorders JAMA Psychiatry 2017 Mar 1;74(3):293-299 intellectual disability J Hum Genet 2019 May;64(5):421-426 Sanders J, Brandsma M, Janssen GM, Dijk J, Möller W. Veremieva M, Khoruzhenko A, Zaicev S, Negrutskii B, Immunofluorescence studies of human fibroblasts El'skaya A. Unbalanced expression of the translation demonstrate the presence of the complex of elongation complex eEF1 subunits in human cardioesophageal factor-1 beta gamma delta in the endoplasmic reticulum J carcinoma Eur J Clin Invest 2011 Mar;41(3):269-76 Cell Sci 1996 May;109 ( Pt 5):1113-7 Wain LV, Pedroso I, Landers JE, Breen G, Shaw CE, Leigh Sanders J, Raggiaschi R, Morales J, Möller W. The human PN, Brown RH, Tobin MD, Al-Chalabi A. The role of copy leucine zipper-containing guanine-nucleotide exchange number variation in susceptibility to amyotrophic lateral protein elongation factor-1 delta Biochim Biophys Acta sclerosis: genome-wide association study and comparison 1993 Jul 18;1174(1):87-90 with published loci PLoS One 2009 Dec 4;4(12):e8175 Sanz-Pamplona R, Arags R, et al. Expression of Wu C, Wyatt AW, McPherson A, Lin D, McConeghy BJ, Mo endoplasmic reticulum stress proteins is a candidate F, Shukin R, Lapuk AV, Jones SJ, Zhao Y, Marra MA, marker of brain metastasis in both ErbB-2+ and ErbB-2- Gleave ME, Volik SV, Wang Y, Sahinalp SC, Collins CC. primary breast tumors Am J Pathol 2011 Aug;179(2):564- Poly-gene fusion transcripts and chromothripsis in prostate 79 cancer Genes Chromosomes Cancer 2012 Dec;51(12):1144-53 Schulte EC, Ellwanger DC, Dihanich S, Manzoni C, Stangl K, Schormair B, Graf E, Eck S, Mollenhauer B, Wu H, Shi Y, Lin Y, Qian W, Yu Y, Huo K. Eukaryotic Haubenberger D, Pirker W, Zimprich A, Brücke T, Lichtner translation elongation factor 1 delta inhibits the ubiquitin P, Peters A, Gieger C, Trenkwalder C, Mewes HW, ligase activity of SIAH-1 Mol Cell Biochem 2011 Nov;357(1- Meitinger T, Lewis PA, Klünemann HH, Winkelmann J. 2):209-15 Rare variants in LRRK1 and Parkinson's disease Neurogenetics 2014 Mar;15(1):49-57 Yang S, Du J, Wang Z, Yuan W, Qiao Y, Zhang M, Zhang J, Gao S, Yin J, Sun B, Zhu T. BMP-6 promotes E-cadherin Shahba S, Jafari Shakib R, Jamshidi A, Vojdanian M, expression through repressing deltaEF1 in breast cancer Akhtari M, Aslani S, Poursani S, Nikokar I, Mahmoudi M. cells BMC Cancer 2007 Nov 13;7:211 Association study of copy number variation in BMP8A gene with the risk of ankylosing spondylitis in Iranian population J Yoshihara K, Wang Q, Torres-Garcia W, Zheng S, Vegesna Cell Biochem 2018 Nov 28 R, Kim H, Verhaak RG. The landscape and therapeutic relevance of cancer-associated transcript fusions Shen H, Huang J, Pei H, Zeng S, Tao Y, Shen L, Zeng L, Oncogene 2015 Sep 10;34(37):4845-54 Zhu H. Comparative proteomic study for profiling differentially expressed proteins between Chinese left- and Zhang D, Chen P, Zheng CH, Xia J. Identification of ovarian right-sided colon cancers Cancer Sci 2013 Jan;104(1):135- cancer subtype-specific network modules and candidate 41 drivers through an integrative genomics approach Oncotarget 2016 Jan 26;7(4):4298-309 Sheu GT, Traugh JA. Recombinant subunits of mammalian elongation factor 1 expressed in Escherichia coli Subunit de Bont JM, Packer RJ, Michiels EM, den Boer ML, Pieters interactions, elongation activity, and phosphorylation by R. Biological background of pediatric medulloblastoma and protein kinase CKII J Biol Chem ependymoma: a review from a translational research perspective Neuro Oncol 2008 Dec;10(6):1040-60 Shuda M, Kondoh N, Tanaka K, Ryo A, Wakatsuki T, Hada A, Goseki N, Igari T, Hatsuse K, Aihara T, Horiuchi S, van 't Veer LJ, Dai H, et al. Gene expression profiling Shichita M, Yamamoto N, Yamamoto M. Enhanced predicts clinical outcome of breast cancer Nature 2002 Jan expression of translation factor mRNAs in hepatocellular 31;415(6871):530-6 carcinoma Anticancer Res 2000 Jul-Aug;20(4):2489-94 This article should be referenced as such: Sinha P, Kohl S, Fischer J, Hütter G, Kern M, Köttgen E, Dietel M, Lage H, Schnölzer M, Schadendorf D. Cristiano L. EEF1D (eukaryotic translation elongation Identification of novel proteins associated with the factor 1 delta). 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Leukaemia Section Review t(6;11)(q13;q12) EEF1G/OOEP Luigi Cristiano Aesthetic and medical biotechnologies research unit, Prestige, Terranuova Bracciolini, Italy; [email protected]; [email protected]

Published in Atlas Database: March 2019 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0611q13q12EEF1G-OOEPID1844.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70679/03-2019-t0611q13q12EEF1G-OOEPID1844.pdf DOI: 10.4267/2042/70679 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology

aberrations, such as frequently chromosomal Abstract translocations, that bring to the formation of many Review on the translocation t(6;11)(q13;q12) in-frame fusion genes encoding the respective EEF1G/OOEP involving EEF1G (alias, eukaryotic chimeric and oncogenic proteins (Atak et al., 2013). translation elongation factor 1 gamma) gene and Among all these chromosomal aberrations it was OOEP (alias, oocyte expressed protein) gene. The found also the fusion gene 5' EEF1G / 3' OOEP novel fusion gene was detected in acute deriving by the genomic translocation and fusion of lymphoblastic leukemia/lymphoblastic lymphoma a part of OOEP gene, situated on chromosome 6, patients but the presence of the correspondent with a portion of EEF1G gene, instead located on protein is still unknown. chromosome 11. This leads to the know but not still Keywords well-characterized translocation t(6;11)(q13;q12) EEF1G/OOEP. Chromosome 6; chromosome 11; EEF1G; eukaryotic translation elongation factor 1 gamma; Prognosis EF1G, GIG35, PRO1608, EEF1γ, EEF1Bγ, EEF-1B There is no evidence of impact of the EEF1G/OOEP gamma, EF-1-gamma, elongation factor 1-gamma, fusion gene on the tumor behavior and also its translation elongation factor EEF-1 gamma chain, contribute in the prognosis of acute lymphoblastic pancreatic tumor-related protein; OOEP, oocyte leukemia/lymphoblastic lymphoma is still unknown. expressed protein, chromosome 6 open reading frame 156, C6orf156, FLOPED, KH homology domain-containing protein 2, KHDC2, oocyte- and Genes involved and embryo-specific protein 19, MOEP19, proteins t(6;11)(q13;q12), acute lymphoblastic leukemia/lymphoblastic lymphoma EEF1G Location 11q12.3 Clinics and pathology Alias: Eukaryotic translation elongation factor 1 Disease gamma, EF1G, GIG35, PRO1608, EEF1γ, EEF1Bγ, EEF-1B Gamma, EF-1-Gamma, Elongation Factor Acute lymphoblastic leukemia/lymphoblastic 1-Gamma, Translation Elongation Factor EEF-1 lymphoma Gamma Chain, Pancreatic Tumor-Related Protein Note Eukaryotic translation elongation factor 1 gamma is T-cell acute lymphoblastic leukemia (T-ALL) a protein that plays a main function in the elongation affects about 15% of pediatric patients and 25% of step of translation process but also covers numerous adult patients of total ALL cases. It is an aggressive moonlighting roles. tumor characterized by the accumulation of multiple genomic mutations and chromosomal

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(3) 136 t(6;11)(q13;q12) EEF1G/OOEP Cristiano L

Figure 1. Schematic representation of the EEF1G gene, OOEP gene and the novel eEF1G-OOEP fusion gene. In the upper side of the picture there are the genomic sequence of EEF1G and OOEP genes, while in the middle side is reported the chimeric fusion gene 5'EEF1G / 3'OOEP. The genomic sequence for EEF1G/OOEP reported by Atak and colleagues (Atak et al., 2013) was analyzed with BlastN. The red portion is derived by EEF1G while the blue piece is derived by OOEP. Violet fraction is the overlapping between the two sequences. Finally, on the bottom side of the image there is the mRNA of EEF1G/OOEP with the predicted coding sequence (CDS) and UTRs (http://insilico.ehu.es/translate/index2.php).

It is expressed ubiquitously in human tissues and roles) inside the cell such as the interaction with often it is found over-expressed in human cancer cytoskeleton and binding with various mRNA and samples and cancer cell lines. several proteins, comprise membrane-bound DNA/RNA receptors (Coumans et al., 2014; Corbi et al., 2010; EEF1G (Eukaryotic Translation Elongation Factor 1 Cho et al., 2003). Gamma) is a protein coding gene with 10 exons and OOEP a length of 14388 bp (RefSeq NC_000011.10). Its Location 6q13 transcript is 1446 bp long (RefSeq NM_001404.5) Alias: oocyte expressed protein, chromosome 6 open but was observed five splice variants and nine reading frame 156, C6orf156, FLOPED, KH pseudogenes probably originated by homology domain-containing protein 2, KHDC2, retrotransposition. oocyte- and embryo-specific protein 19, MOEP19. Protein DNA/RNA eEF1G is formed by 437 amino acids (RefSeq OOEP gene is composed by 3 exons (RefSeq NP_001395.1), it has a molecular weight of 50.12 NC_000006.12) and its transcript is 689 nt long kDa and it is a multi-domain protein which consist (RefSeq NM_001080507). of three main domains: from the amino to carboxyl half terminal there are a glutathione S-transferase Protein (GST)-like N-terminus domain (NT-eEF1G), a Oocyte expressed protein, alias OOEP, is a glutathione S-transferase (GST)-like C-terminus component of the subcortical maternal complex domain (CT-eEF1G) and a conserved C-terminal (SCMC) that plays its roles in oocytes and in early domain (CD-eEF1G) (Achilonu et al.,2014). stages of embryogenesis (Bebbere et al., 2016). eEF1G is a subunit of the eukaryotic elongation OOEP is formed by 149 amino acids (RefSeq factor-1 complex named eEF1H that result by the NP_001073976) and it has a molecular weight of aggregation of different proteins that play a central 17.17 kDa. There are known other two isoforms of role in peptide elongation during eukaryotic protein OOEP but their roles are unclearly. biosynthesis. The physiological role of eEF1G is still not well defined, however eEF1G seems to be Result of the chromosomal necessary for guarantee the stability to entire eEF1H anomaly complex and to stimulate the activity of the eEF1B2 subunit during the elongation step of translation Hybrid gene (Mansilla et al., 2002). However, are known that it The result of chromosomal anomaly is the novel has multiple non-canonical roles (moonlighting fusion gene 5' EEF1G / 3' OOEP. Atak and

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t(6;11)(q13;q12) EEF1G/OOEP Cristiano L

colleagues (Atak et al., 2013) found its DNA in T- formed by both the non-coding 5'UTR and 3'UTR cell acute lymphoblastic leukemia (T-ALL), but and a coding sequence (CDS). The CDS is among there are no data or evidence about its mRNA and its 221 and 374 nt with a length of 154 nt and it is protein. So, in this review, with the use of various apparently protein-coding. It was chosen the longer tools and software will be predicted the possible codifying sequence of the 5'->3' strand in that the transcript and also the probable protein. However, sequence offers more reading possibilities the data collected are hypothesis and have to be (https://www.ncbi.nlm.nih.gov/orffinder/). experimental verified. Fusion protein Description The fusion gene 5' EEF1G / 3' OOEP was found in Description T-cell acute lymphoblastic leukemia (T-ALL) (Atak There is no evidence about the protein of the et al., 2013) and it derives by the genomic EEF1G/OOEP fusion gene. However, with translocation t(6;11)(q13;q12) EEF1G/OOEP, i.e. INSILICO and ORFFINDER tools by fusion of a part of OOEP gene, situated on (http://insilico.ehu.es/translate/index2.php; chromosome 6, with a portion of EEF1G gene, https://www.ncbi.nlm.nih.gov/orffinder/) is possible instead located on chromosome 11. to predict the protein sequence of the EEF1G/OOEP In particular, the fusion interests part of exon 8 and mRNA. exon 7 of EEF1G that result fused with a portion of The protein counts 51 amino acids with a molecular the second intron sequence, i.e. intron 2-3, of the mass of 6,41 kDa and a theoretical pI of 12.55 OOEP-202, an alternative splicing form of OOEP (https://web.expasy.org/cgi-bin/protparam/ that contains also the ribosomal protein L39 protparam). Surprisingly a perfect sequence pseudogene 3, alias RPL39P3 homology with ribosomal L39 protein (RPL39) is (https://www.ensembl.org). noted by BlastP analysis and can be found the By the analysis of the sequences reported in Ensembl ribosomal L39 putative domain appears that the portion of the OOEP gene that is (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The post- fused with EEF1G is really a portion of RPL39P3 translational modifications are unknown. pseudogene. Expression / Localisation Transcript There is no evidence not only of the protein but also There is no evidence about the mRNA of the of its localization. However, the predicted sub- EEF1G/OOEP fusion gene. However, with cellular localization for the protein is cytoplasm bioinformatic tools it is possible to predict its (http://linux1.softberry.com/cgi- sequence and characterizing it. It seems to be bin/programs/proloc/protcompan.pl).

Figure.2 Schematic representation of protein produced by EEF1G/OOEP fusion gene. [1] In the upper side of the image there are both the structure of EEF1G/OOEP mRNA and the primary sequence of the translated protein (predicted); [2] in the middle side of the image are reported both the main domain of the protein which corresponds to ribosomal L39 protein (RPL39) putative domain and the predicted secondary structure (http://www.jalview.org); [3] the predicted tertiary structure for the protein, homologous to RPL39, is reported (https://swissmodel.expasy.org).

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Oncogenesis Foà R, Speleman F, Cools J, Aerts S. Comprehensive analysis of transcriptome variation uncovers known and It is unclear the role in oncogenesis of the novel driver events in T-cell acute lymphoblastic leukemia. translocation t(6;11)(q13;q12) EEF1G/OOEP and PLoS Genet. 2013;9(12):e1003997 there is no evidence about its effective transcription Bebbere D, Masala L, Albertini DF, Ledda S. The and/or translation. Perhaps the EEF1G/OOEP subcortical maternal complex: multiple functions for one fusion gene plays a regulatory role or it is instead biological structure? J Assist Reprod Genet. 2016 effectively translated into a functional protein, that Nov;33(11):1431-1438 by bioinformatic analysis seems to be RPL39-like Chen M, Xu R, Ji H, Greening DW, Rai A, Izumikawa K, protein and that deriving from RPL39P3 Ishikawa H, Takahashi N, Simpson RJ. Transcriptome and pseudogene. It was demonstrated that RPL39 plays a long noncoding RNA sequencing of three extracellular vesicle subtypes released from the human colon cancer role in metaplastic breast cancer where shows an LIM1863 cell line. Sci Rep. 2016 Dec 5;6:38397 oncogenic activity through the increase of the Cho DI, Oak MH, Yang HJ, Choi HK, Janssen GM, Kim KM. inducible nitric oxide synthase ( NOS2). Moreover, Direct and biochemical interaction between dopamine D3 it was evidenced that a high RPL39 and iNOS receptor and elongation factor-1Bbetagamma. Life Sci. expression are associated with a reduction in patient 2003 Oct 24;73(23):2991-3004 overall survival (Dave et al., 2017), so the abnormal Corbi N, Batassa EM, Pisani C, Onori A, Di Certo MG, translocation t(6;11)(q13;q12) EEF1G/OOEP could Strimpakos G, Fanciulli M, Mattei E, Passananti C. The be linked with an increase of RPL39 levels in acute eEF1γ subunit contacts RNA polymerase II and binds lymphoblastic leukemia/lymphoblastic lymphoma vimentin promoter region. PLoS One. 2010 Dec 31;5(12):e14481 cancer cells by the translation of its pseudogene RPL39P3. In addition, some authors found high Coumans JV, Gau D, Poljak A, Wasinger V, Roy P, Moens expression of RPL39P3 in human colon cancer P. Green fluorescent protein expression triggers proteome changes in breast cancer cells Exp Cell Res 2014 Jan LIM1863 cell line (Chen et al., 2016). 1;320(1):33-45 However, these are only hypothesis and the truly Dave B, Gonzalez DD, Liu ZB, Li X, Wong H, Granados S, oncogenic potential of EEF1G/OOEP in Ezzedine NE, Sieglaff DH, Ensor JE, Miller KD, Radovich proliferation and cancer aggressiveness needs to be M, KarinaEtrovic A, Gross SS, Elemento O, Mills GB, better elucidated. Gilcrease MZ, Chang JC. Role of RPL39 in Metaplastic Breast Cancer J Natl Cancer Inst 2016 Dec 31;109(6) References Mansilla F, Friis I, Jadidi M, Nielsen KM, Clark BF, Knudsen CR. Mapping the human translation elongation factor Achilonu I, Siganunu TP, Dirr HW. Purification and eEF1H complex using the yeast two-hybrid system Biochem characterisation of recombinant human eukaryotic J 2002 Aug 1;365(Pt 3):669-76 elongation factor 1 gamma. Protein Expr Purif. 2014 Jul;99:70-7 This article should be referenced as such: Atak ZK, Gianfelici V, Hulselmans G, De Keersmaecker K, Cristiano L. t(6;11)(q13;q12) EEF1G/OOEP. Atlas Genet Devasia AG, Geerdens E, Mentens N, Chiaretti S, Durinck Cytogenet Oncol Haematol. 2020; 24(3):136-139. K, Uyttebroeck A, Vandenberghe P, Wlodarska I, Cloos J,

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Leukaemia Section Short Communication

Fibroblastic Reticular Cell Tumor Luis Miguel Juárez Salcedo, Diego Conde Royo, Samir Dalia Gregorio Marañón University General Hospital, Madrid, Spain [email protected] (LMJS); Principe de Asturias University Hospital, Madrid, Spain [email protected] (DCR); Oncology and Hematology, Mercy Clinic Joplin, Joplin, MO, USA [email protected] (SD). Published in Atlas Database: April 2019 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/FibroblasReticulCellID1836.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70680/04-2019-FibroblasReticulCellID1836.pdf DOI: 10.4267/2042/70680 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Phenotype/cell stem origin Dentritic/reticular cells are structural and functional Review on Fibroblastic reticular cell tumor, with accessory cells components of immune system. They data on clinics, and the genes involved. have been subdivided on the bases of their location Keywords and phenotype into 3 major subsets: follicular Fibroblastic Reticular Cell Tumor; Cytokeratin- dendritic cells (FDCs), interdigitating dendritic cells positive interstitial reticulum cell tumor; (IDCs), and fibroblastic reticular cells (FRCs). These Fibroblastic dendritic cell tumor; dendritic cell cells are stromal cells located in the parafollicular sarcoma area and deep cortex of lymph nodes and also in the extrafollicular areas of the spleen and tonsils Identity (Doglioni C, et al., 1990). These cells are crucial to the interaction between IDCs and T cells in the Other names primary immune response (Andriko JW et al., 1998). Cytokeratin-positive interstitial reticulum cell This pathology was also known as cytokeratin- tumor, Fibroblastic dendritic cell tumor positive interstitial reticulum cell tumor. Clinics and pathology Epidemiology Median age for FRCT was 61 years old (range 13-80 Disease years) with slight male predilection. Fibroblastic reticular cell tumor (FRCT) is the rarest Clinics subgroup of dendritic cell sarcoma (DCS) with few Information about FRCT generally comes from cases published in the literature (Kwon JE et series of isolated patients mainly reported in the al.,2009; Dalia S et al., 2013). manuscripts by Saygin C et al and Dalia S et al. Both Fibroblastic reticular cells are stromal support cells papers reported that isolated nodal disease is more located in the parafollicular are and deep cortex of common (84.2%) when compared to other lymph nodes and in the extrafollicular areas of the pathological entities. Cervical and mediastinal spleen and tonsils. (Andriko JW et al., 1998). lymph nodes were the ones most commonly In general, FRCT are presents in the lymph nodes, involved during disease course. Extranodal sites but also in the spleen, lung, liver, and soft tissue included the liver, lung, kidney, adrenal, bone, and (Martel M et al., 2003). soft tissue. Higher-stage disease has a significantly Most of the patients presented with a localized shorter survival rate. Patients with local disease had disease, and stage have an important effect in the a 2-year survival rate of 85.7%; median survival overall survivor of patients.

was not reached.

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(3) 140 Fibroblastic Reticular Cell Tumor. Juárez-Salcedo LM et al.

Patients with distant disease died in 2 years and had care centers. a median survival rate of one year (Saygin C et al.,2013). Most patients present with a newly References diagnosed asymptomatic mass that was surgically Andriko JW, Kaldjian EP, Tsokos M, Abbondanzo SL, Jaffe removed (Saygin C et al., 2013, Martel M et at., ES. Reticulum cell neoplasms of lymph nodes: a 2003). clinicopathologic study of 11 cases with recognition of a new Diagnosis The value of CT scans, bone marrow subtype derived from fibroblastic reticular cells. Am J Surg biopsy, and other staging work in single nodal Pathol. 1998 Sep;22(9):1048-58 disease is unknown, but it becomes important in Dalia S, Shao H, Sagatys E, Cualing H, Sokol L. Dendritic patients with multiple enlarged lymph nodes. cell and histiocytic neoplasms: biology, diagnosis, and Excisional biopsy of the lymph node is the gold- treatment. Cancer Control. 2014 Oct;21(4):290-300 standard diagnostic method for FRCT. Doglioni C, Dell'Orto P, Zanetti G, Iuzzolino P, Coggi G, Viale G. Cytokeratin-immunoreactive cells of human lymph Pathology nodes and spleen in normal and pathological conditions. An Morphologically this disorder is described as spindle immunocytochemical study. Virchows Arch A Pathol Anat Histopathol. 1990;416(6):479-90 to ovoid cells with whorls in the paracortical areas associated with abundant reticulin staining fibers. Gould VE, Bloom KJ, Franke WW, Warren WH, Moll R. Increased numbers of cytokeratin-positive interstitial Immunohistochemistry is positive for vimentin, reticulum cells (CIRC) in reactive, inflammatory and desmin factor XIIIa, and smooth muscle actin. neoplastic lymphadenopathies: hyperplasia or induced CD45RB, CD21, CD35, S100, CD65, and CD1a are expression? Virchows Arch. 1995;425(6):617-29 negative (Saygin C et al., 2013). Ultraestructural Kwon JE, Yang WI, Kim HK, Kwon KW, Kwon TJ, Choi EC, evaluation reveals peripherally located fusiform Lee KG. Cytokeratin-positive interstitial reticulum cell densities, long cytoplasmic extension, and sarcoma: a case report with cytological, desmosomal-like intercellular attachments (Dalia S immunohistochemical, and ultrastructural findings. Cytopathology. 2009 Jun;20(3):202-5 et al., 2013). A subset of fibroblastic reticulum cells that express cytokeratine 8 and 18 and various other Martel M, Sarli D, Colecchia M, Coppa J, Romito R, Schiavo M, Mazzaferro V, Rosai J. Fibroblastic reticular cell tumor of epithelial markers has been identified. (Golud VE et the spleen: report of a case and review of the entity. Hum al., 1995). Pathol. 2003 Sep;34(9):954-7 Treatment Saygin C, Uzunaslan D, Ozguroglu M, Senocak M, Tuzuner N. Dendritic cell sarcoma: a pooled analysis including 462 Surgery is the treatment of choice for patients with cases with presentation of our case series. Crit Rev Oncol localized disease. Limited data exist about the role of Hematol. 2013 Nov;88(2):253-71 the radiotherapy. In localized disease, chemotherapy is not indicated. Patient should be included in This article should be referenced as such: clinical trials or referred to specialized Juárez-Salcedo LM, Conde Royo D, Dalia S. Fibroblastic Reticular Cell Tumor. Atlas Genet Cytogenet Oncol Haematol. 2020; 24(3):140-141.

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Leukaemia Section Short Communication t(1;19)(q22;p13.2) MEF2D/DAZAP1 Tatiana Gindina R.M. Gorbacheva Memorial Institute of Children Oncology Hematology and Transplantation at First Pavlov Saint-Petersburg State Medical University, Saint-Petersburg, Russia / [email protected] Published in Atlas Database: May 2019 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0119MEF2DDAZAP1ID1843.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70681/05-2019-t0119MEF2DDAZAP1ID1843.pdf DOI: 10.4267/2042/70681 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology

induced genes. Abstract A remarkable increase in expression levels of MEF2A and MEF2D has been reported during Review on t(1;19)(q22;p13.2) MEF2D/DAZAP1, differentiation into monocytes using the promyeloid with data on the genes involved HL-60 cell line (Yuki et al., 2004). Keywords In mouse models, MEF2D was identified as a Chromosome 1 ; Chromosome 19 ; candidate oncogene involved in the pathogenesis of t(1;19)(q22;p13.3) ; MEF2D ; DAZAP1 ; leukemia. It is assumed, that native MEF2D has latent Clinics and pathology transforming properties, which can be unmasked via aberrant protein expression (Prima et al., 2005). Disease B lymphoblastic leukemia DAZAP1 (Deleted in Azoospermia- Associated Protein 1) Epidemiology Only one case to date: a 3-year-old female child Location 19p13.3 (Yuki et al., 2004; Prima et al., 2005; Liu et al., Protein 2016). DAZAP1 is an RNA binding protein, which contains two RNA-recognition motifs (RRMs), a proline-rich Cytogenetics C-terminal portion and expressed most abundantly in the testis during spermatogenesis, and to a lower The cells carry t(1;19) but lack TCF3 (E2A) level, in the thymus. rearrangements and do not express E2A/ PBX1. Genes involved and Result of the chromosomal proteins anomaly Hybrid gene MEF2D (Myocyte Enhancer Factor 2D) Description The genes were fused in-frame between exon 6 of Location 1q22 MEF2D and exon 7 of DAZAP1 Protein (MEF2D/DAZAP1), as well as, between exon 6 of MEF2D belongs to the MADS-box family of DAZAP1 and exon 7 of MEF2D transcription factors; this molecule binds as a homo- (DAZAP1/MEF2D). Sequencing of the RT-PCR or hetero-dimer to the MEF2 element present in the products confirmed in-frame fusions between regulatory regions of numerous muscle-specific and MEF2D (codon 222) and DAZAP1 (codon 155) in growth-factor and stress- both chimeric transcripts (Yuki et al., 2004).

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(3) 142 t(1;19)(q22;p13.2) MEF2D/DAZAP1 Gindina T

Figure 1. Schematic representation of the wild-type MEF2D and DAZAP1 products and of the chimeric fusion proteins MEF2D/DAZAP1 and DAZAP1/MEF2D.

Transcript These alterations may confer more potent Both chimeric transcripts, MEF2D/DAZAP1 and transforming properties to MEF2D/DAZAP1, which DAZAP1/MEF2D, whose sequences indicated in- can be further augmented by coexpression with the frame fusions between MEF2D and DAZAP1 were reciprocal DAZAP1/MEF2D chimera, which retains expressed in bone marrow cells (Yuki et al., 2004). sequence-specific RNA binding properties (Prima et al., 2005). Fusion protein Expression / Localisation References MEF2D/DAZAP1 and DAZAP1/MEF2D proteins Liu YF, Wang BY, Zhang WN, Huang JY, Li BS, Zhang M, were both located in the nucleus, MEF2D/DAZAP1 Jiang L, Li JF, Wang MJ, Dai YJ, Zhang ZG, Wang Q, Kong was able to form dimers with MEF2D and HDAC4. J, Chen B, Zhu YM, Weng XQ, Shen ZX, Li JM, Wang J, Furthermore, exogenous expression of Yan XJ, Li Y, Liang YM, Liu L, Chen XQ, Zhang WG, Yan MEF2D/DAZAP1 and DAZAP1/MEF2D promoted JS, Hu JD, Shen SH, Chen J, Gu LJ, Pei D, Li Y, Wu G, Zhou X, Ren RB, Cheng C, Yang JJ, Wang KK, Wang SY, the growth of HeLa cells (Yuki et al., 2004). Zhang J, Mi JQ, Pui CH, Tang JY, Chen Z, Chen SJ. Oncogenesis Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia. EBioMedicine. 2016 Jun;8:173- MEF2D/DAZAP1 and/or DAZAP1/MEF2D 183 contribute to leukemogenesis by altering signaling pathways normally regulated by wild-type MEF2D Prima V, Gore L, Caires A, Boomer T, Yoshinari M, Imaizumi M, Varella-Garcia M, Hunger SP. Cloning and and DAZAP1. MEF2D/DAZAP1 binds avidly and functional characterization of MEF2D/DAZAP1 and specifically to DNA and is a substantially more DAZAP1/MEF2D fusion proteins created by a variant potent transcriptional activator, than MEF2D and t(1;19)(q23;p13.3) in acute lymphoblastic leukemia. also may associate more strongly with other proteins Leukemia. 2005 May;19(5):806-13 involved in transcriptional regulation (e.g. HDAC4). Yuki Y, Imoto I, Imaizumi M, Hibi S, Kaneko Y, Amagasa T, MEF2D/DAZAP1 might immediately activate Inazawa J. Identification of a novel fusion gene in a pre-B acute lymphoblastic leukemia with t(1;19)(q23;p13). Cancer transcription of genes crucial for lymphocyte growth Sci. 2004 Jun;95(6):503-7 and/or survival such as IL2 (interleukin-2), a known transcriptional target of MEF2D in T-cells. As well, This article should be referenced as such: MEF2D/DAZAP1 could contribute to Gindina T. t(1;19)(q22;p13.2) MEF2D/DAZAP1. Atlas leukemogenesis via dysregulated activation of Genet Cytogenet Oncol Haematol. 2020; 24(3):142-143. MAPK-mediated cell proliferation pathways.

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Leukaemia Section Short Communication t(1;19)(q22;p13.2) MEF2D/HNRNPUL1 Tatiana Gindina R.M. Gorbacheva Memorial Institute of Children Oncology Hematology and Transplantation at First Pavlov Saint-Petersburg State Medical University, Saint-Petersburg, Russia / [email protected]

Published in Atlas Database: May 2019 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0119q22p13ID1830.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70682/05-2019-t0119q22p13ID1830.pdf DOI: 10.4267/2042/70682 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Protein MEF2D belongs to the MADS-box family of Review on t(1;19)(q22;p13.2), with data on the transcription factors; this molecule binds as a homo- genes involved or hetero-dimer to the MEF2 element present in the Keywords regulatory regions of numerous muscle-specific and Chromosome 1 ; Chromosome 19 ; growth-factor and stress-induced genes. A t(1;19)(q22;p13.2) ; MEF2D ; HNRNPUL1 ; remarkable increase in expression levels of MEF2A and MEF2D has been reported during differentiation Clinics and pathology into monocytes using the promyeloid HL-60 cell line (Yuki et al., 2004). In mouse models, MEF2D was Disease identified as a candidate oncogene involved in the B progenitor acute lymphoblastic leukemia. pathogenesis of leukemia. It is assumed, that native MEF2D has latent transforming properties, which Phenotype/cell stem origin can be unmasked via aberrant protein expression The immunophenotype of MEF2D-rearranged ALL (Prima et al., 2005). is characterized by weak or absent expression of HNRNPUL1 (Heterogeneous nuclear CD10 and high expression of CD38, but these features are uncommon in B-cell precursor ALL (Gu ribonucleoprotein U-like 1) et al., 2016). Location 19p13.2 Epidemiology Protein Only 8 cases to date (Gu et al., 2016; Lilljebjorn et HNRNPUL1 is a nuclear RNA-binding protein al., 2016; Liu et al., 2016; Yasuda et al., 2016). which belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family. HNRNPUL1 Prognosis acts as a basic transcriptional regulator and may The outcome of MEF2D-rearranged ALL was exert a role in mRNA processing, nucleocytoplasmic inferior to that of other ALL subtypes (Gu et al., RNA transport and DNA repair. 2016). Result of the chromosomal Genes involved and anomaly proteins Hybrid gene MEF2D (Myocyte Enhancer Factor Description 2D) The genes were fused in-frame between exon 8 of Location 1q22

MEF2D and exon 12 of HNRNPUL1.

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Fusion protein Schrappe M, Cario G, Castor A, Pronk CJ, Behrendtz M, Mitelman F, Johansson B, Paulsson K, Andersson AK, Description Fontes M, Fioretos T. Identification of ETV6-RUNX1-like The amino terminus of MEF2D was fused in frame and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia. Nat Commun. with the carboxy-terminal portion of HNRNPUL1. 2016 Jun 6;7:11790 Oncogenesis Liu YF, Wang BY, Zhang WN, Huang JY, Li BS, Zhang M, MEF2D/HNRNPUL1 fusion preserves the MEF2D Jiang L, Li JF, Wang MJ, Dai YJ, Zhang ZG, Wang Q, Kong MADS-box domain that mediates DNA binding and J, Chen B, Zhu YM, Weng XQ, Shen ZX, Li JM, Wang J, potentially dimerization. Thereby, aberrant function Yan XJ, Li Y, Liang YM, Liu L, Chen XQ, Zhang WG, Yan JS, Hu JD, Shen SH, Chen J, Gu LJ, Pei D, Li Y, Wu G, mediated by MEF2D transcriptional activation is Zhou X, Ren RB, Cheng C, Yang JJ, Wang KK, Wang SY, likely to be central in leukaemogenesis. The Zhang J, Mi JQ, Pui CH, Tang JY, Chen Z, Chen SJ. MEF2D/HNRNPUL1 fusion protein was Genomic Profiling of Adult and Pediatric B-cell Acute significantly more potent in activating expression Lymphoblastic Leukemia. EBioMedicine. 2016 Jun;8:173- 183 than wild-type MEF2D. The rearrangement results in enhanced MEF2D transcriptional activity, Prima V, Gore L, Caires A, Boomer T, Yoshinari M, lymphoid transformation, activation of HDAC9 Imaizumi M, Varella-Garcia M, Hunger SP. Cloning and functional characterization of MEF2D/DAZAP1 and expression and sensitivity to histone deacetylase DAZAP1/MEF2D fusion proteins created by a variant inhibitor treatment (Gu et al., 2016). t(1;19)(q23;p13.3) in acute lymphoblastic leukemia. Leukemia. 2005 May;19(5):806-13 References Yasuda T, Tsuzuki S, Kawazu M, Hayakawa F, Kojima S, Ueno T, Imoto N, Kohsaka S, Kunita A, Doi K, Sakura T, Gu Z, Churchman M, Roberts K, Li Y, Liu Y, Harvey RC, Yujiri T, Kondo E, Fujimaki K, Ueda Y, Aoyama Y, Ohtake McCastlain K, Reshmi SC, Payne-Turner D, Iacobucci I, S, Takita J, Sai E, Taniwaki M, Kurokawa M, Morishita S, Shao Y, Chen IM, Valentine M, Pei D, Mungall KL, Mungall Fukayama M, Kiyoi H, Miyazaki Y, Naoe T, Mano H. AJ, Ma Y, Moore R, Marra M, Stonerock E, Gastier-Foster Recurrent DUX4 fusions in B cell acute lymphoblastic JM, Devidas M, Dai Y, Wood B, Borowitz M, Larsen EE, leukemia of adolescents and young adults Nat Genet 2016 Maloney K, Mattano LA Jr, Angiolillo A, Salzer WL, Burke May;48(5):569-74 MJ, Gianni F, Spinelli O, Radich JP, Minden MD, Moorman AV, Patel B, Fielding AK, Rowe JM, Luger SM, Bhatia R, Yuki Y, Imoto I, Imaizumi M, Hibi S, Kaneko Y, Amagasa T, Aldoss I, Forman SJ, Kohlschmidt J, Mrózek K, Marcucci G, Inazawa J. Identification of a novel fusion gene in a pre-B Bloomfield CD, Stock W, Kornblau S, Kantarjian HM, acute lymphoblastic leukemia with t(1;19)(q23;p13) Cancer Konopleva M, Paietta E, Willman CL, Loh ML, Hunger SP, Sci 2004 Jun;95(6):503-7 Mullighan CG. Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia. Nat Commun. This article should be referenced as such: 2016 Nov 8;7:13331 Gindina T. t(1;19)(q22;p13.2) MEF2D/HNRNPUL1. Atlas Lilljebjörn H, Henningsson R, Hyrenius-Wittsten A, Olsson Genet Cytogenet Oncol Haematol. 2020; 24(3):144-145. L, Orsmark-Pietras C, von Palffy S, Askmyr M, Rissler M,

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Leukaemia Section Review

Langerhans cell histiocytosis Ding-Bao Chen Department of Pathology, Peking University People's Hospital, Beijing 100044, People's Republic of China; [email protected] Published in Atlas Database: June 2019 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/LangerhansHistiocytosisID1730.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70683/06-2019-LangerhansHistiocytosisID1730.pdf DOI: 10.4267/2042/70683

cells that express CD1a, langerin, and S100 protein, Abstract showing Birbeck granules by ultrastructural Tumours derived from Langerhans cells (LCs) are examination (Swerdlow, et al ,2008. Swerdlow, et al, divided into two main subgroups, according to the 2016). degree of cytological atypia and clinical Phenotype/cell stem origin aggressiveness: LC histiocytosis (LCH) and LC sarcoma. Both subgroups maintain the phenotypic The neoplastic cells of LCH consistently expresses profile and ultrastructural features of LCs. LCH is a CD1a, langerin, and S100 protein (Chikwava, et al, clonal neoplastic proliferation of Langerhans-type 2004). In addition, the cells are positive for vimentin, cells that express CD1a, langerin, and S100 protein, CD68, and HLA-DR. CD45 expression and showing Birbeck granules by ultrastructural lysozyme content is low. B-cell and T-cell lineage examination. Here the clinicopathological of LCH markers (except for CD4), CD30, and follicular will be discussed. dendritic cell markers are negative. The Ki-67 proliferation index is highly variable (Pileri, et al Keywords ,2002). Expression of PDL1 is seen in many cases. Langerhans cell histiocytosis; CD1a; The Langerhans cells are derived from mononuclear immunophenotype; Cytogenetics phagocytes macrophages and dendritic cells) or histiocytes. (Swerdlow, et al ,2008; Swerdlow, et al Identity ,2016. ) Other names Epidemiology Langerhans cell granulomatosis, Solitary lesion: The annual incidence is about 5 cases per 1 million histiocytosis X, Eosinophilic granuloma; multiple population, with most cases occurring in childhood. lesions: Hand- Schüller- Christian disease. Cases There is a male predilection, with a male-to- female with disseminated or visceral involvement: Letterer- ratio of 3.7:1. The disease is more common in white Siwe disease populations of northern European descent and rare in black populations. Primary LCH of the lung is Clinics and pathology almost always a disease of smokers, predominantly in young smokers, without gender predominance Disease (Swerdlow, et al , 2008; Swerdlow, et al ,2016. Tumours derived from Langerhans cells (LCs) are Radzikowska, 2017). divided into two main subgroups, according to the degree of cytological atypia and clinical Clinics aggressiveness: LC histiocytosis (LCH) and LC Patients with unifocal disease are usually older sarcoma. Both subgroups maintain the phenotypic children or adults who most commonly present with profile and ultrastructural features of LCs. LCH is a a lytic bone lesion eroding the cortex. Solitary clonal neoplastic proliferation of Langerhans-type lesions at other sites present as mass lesions or

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enlarged lymph nodes. Patients with unisystem Spleen shows nodular red pulp involvement. Large multifocal disease are usually young children who clusters or sheets of LCH cells accompanied by present with multiple or sequential destructive bone eosinophils can be found within other lesions lesions, often associated with adjacent soft tissue (lymphomas and sarcomas). It remains to be masses. Skull and mandibular involvement is determined whether these constitute a local reactive common. Patients with multisystem involvement are phenomenon or a trans-differentiation process. The infants who present with fever, cytopenias, skin and ultrastructural hallmark is the cytoplasmic Birbeck bone lesions, and hepatosplenomegaly. There is an granules, whose presence can be confirmed by association between LCH and T-lymphoblastic langerin expression. The Birbeck granule has a leukaemia, with the leukaemia-associated TCR gene tennis-racket shape, and is 200-400 nm long and 33 rearrangement present in the LCH cells, which has nm wide, with a zipper-like appearance. been considered as a trans-differentiation phenomenon. The disease can be localized to a single site, can occur in multiple sites within a single system (usually bone), or can be more disseminated and multisystem. The dominant sites of involvement in the solitary form are bone and adjacent soft tissue (skull, femur, vertebra, pelvic bones, and ribs) and, less commonly, lymph node, skin, and lung. Multifocal lesions are largely confined to bone and adjacent soft tissue. In multisystem disease, the skin, bone, liver, spleen, and bone marrow are the preferential sites of involvement (Swerdlow, et al ,2008; Swerdlow, et al ,2016). Pathology The LCH cells are oval, about 10-15 µm, with grooved, folded, indented, or lobed nuclei and fine chromatin, inconspicuous nucleoli, thin nuclear membranes. Nuclear atypia is minimal, but mitotic activity is variable and can be high. The cytoplasm is moderately abundant and slightly eosinophilic. LCH cells are devoid of dendritic cell processes. The characteristic milieu includes a variable number of eosinophils, histiocytes (both multinucleated LCH forms and osteoclast-type cells, especially in bone), neutrophils, and small lymphocytes. Plasma cells are usually absent. Eosinophilic abscesses with central necrosis, rich in Charcot-Leyden crystals can be seen. In early lesions, LCH cells predominate, along with eosinophils and neutrophils. In late lesions, the LCH cells are decreased in number, with increased foamy macrophages and fibrosis. Involved lymph nodes have a sinus pattern with secondary Figure1. Langerhans cell granulomatosis. Radiograph infiltration of the paracortex. from a patient with a discrete punched-out bone lesion in upper femur.

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Langerhans cell histiocytosis. Chen DB

Figure 2. Langerhans cell granulomatosis. There are some Langerhans cells, with linear grooves in nulei and scattered eosinophils, lymphocytes in the background.

Figure 3. Langerhans cell granulomatosis. There are some Langerhans cells, with scattered eosinophils, lymphocytes in the background, and a multinucleated cell can be seen.

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Figure 4. The tumor cells are positive for CD1a in the membrane.

Figure 5. The tumor cells are positive for langerin in the cytoplasm.

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Figure 6. The tumor cells are positive for langerin in the nuclei and cytoplasm. Treatment Pulmonary LCH is based on cladribineor cytarabine as salvage therapy (Radzikowska, 2017). Treatment of LCH depends on the spread of the disease, affected organs, including lesions in critical Basing on extrapolated observations made during organs and the degree of damage. randomised trials in children, various types of Systemic chemotherapy is recommended in the cases cytoreductive therapy (methotrexate, vinblastine, 6 of multisystem LCH, with or without the mercaptopurine, etoposide) have been applied in involvement of critical organs, single system LCH adult LCH patients. However, the disease in adults with multiple lesions and single system LCH with runs a diverse clinical course and many drugs are lesions in specific sites. differently tolerated. Vemurafenib and other BRAF There is no established standard of chemotherapy to inhibitors offer new possibilities for targeted LCH date. therapy in patients with relevant mutations. (Epaud, Although in children chemotherapy with vinblastine 2015; Héritier, 2016). and prednisone proved to be effective, the results of MAP kinase inhibitors (Sorafenib, trametinib and treatment in adults turned out to be less successful. cobimetinib) have been reported to be effective in In patients with multiple bone lesions and affected patients with aggressive form of histiocytosis. lungs, significantly higher effectiveness of treatment Furthermore, it is vital to remember that presented with cytarabine or cladribine compared to mutations in Langerhans' cells are not excluding vinblastine and prednisone has been shown. In some mutations, thus, in particular cases, there are cases with solitary bone involvement, surgical recommendations to apply double targeted therapy removal of the focus is proposed or treatment of (Kolenova, 2017). lesions with steroid injections. Patients with multiple bone lesions are treated systemically, surgically Prognosis and/or with biphosphonates. Smoking cessation is The clinical course is related to staging of the disease the most important recommendation for Pulmonary at presentation, with ≥ 99% survival for unifocal LCH patients. Some authors recommend systemic disease and 66% mortality for young children with steroid therapy in case of intensive symptoms from multisystem involvement who do not respond the respiratory system (Girschikofsky, 2013; promptly to therapy. Involvement of the bone Rigaud, 2016). The treatment of progressive marrow, liver, or lung is considered a high-risk factor. Progression from initial focal disease to

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multisystem involvement can occur, most commonly Vassallo R, Weiss LM. Revised classification of in infants. Patient age, per se, is a less important histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016 Jun 2;127(22):2672-81 indicator than is extent of disease. BRAF V600E mutation does not seem to affect prognosis. Systemic Epaud R, Ducou Le Pointe H, Fasola S, Ploussard S, Delestrain C, Sileo C, Donadieu J. Cladribine improves lung and (rarely) multifocal disease can be complicated cysts and pulmonary function in a child with histiocytosis. by haemophagocytic syndrome (Swerdlow, et al , Eur Respir J. 2015 Mar;45(3):831-3 2008; Swerdlow, et al ,2016). Girschikofsky M, Arico M, Castillo D, Chu A, Doberauer C, Fichter J, Haroche J, Kaltsas GA, Makras P, Marzano AV, Cytogenetics de Menthon M, Micke O, Passoni E, Seegenschmiedt HM, Tazi A, McClain KL. Management of adult patients with LCH has been shown to be clonal by X-linked Langerhans cell histiocytosis: recommendations from an androgen receptor gene (HUMARA) assay, except expert panel on behalf of Euro-Histio-Net. Orphanet J Rare in some adult pulmonary lesions. About 30% of Dis. 2013 May 14;8:72 cases have detectable clonal IGH, IGK, or TR Héritier S, Emile JF, Barkaoui MA, et al.. BRAF Mutation rearrangements, including some cases with both T- Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy. J Clin cell and B-cell gene rearrangements. Approximately Oncol. 2016; 34(25): 3023-3030. 50% of cases harbor BRAF V600E mutation. BRAF V600E mutation has also been identified in 28% of Kolenová A, Schwentner R, Jug G, et al.. Targeted inhibition of the MAPK pathway: emerging salvage option for pulmonary cases, suggesting that at least many of progressive life-threatening multisystem LCH. Blood these cases constitute a clonal proliferation. In Advances. 2017; 1(6): 352-356. addition, about 25% of cases are associated with Pileri SA, Grogan TM, Harris NL, et al.. somatic MAP2K1 mutations, almost always Tumours of histiocytes and accessory dendritic cells: an occurring in BRAF germline cases. Other BRAF immunohistochemical approach to classification from the germline cases may have somatic ARAF mutations International Lymphoma Study Group based on 61 cases. (Swerdlow, et al ,2008; Swerdlow, et al ,2016). Histopathology. 2002 Jul;41(1):1-29. Mutations affecting other signaling pathway such as Radzikowska E.. Pulmonary Langerhans' cell histiocytosis PIK3CA, PICK1, and PICK3R2 have also been in adults. Advances in Respiratory Medicine 2017, vol. 85, described in LCH. (Emile, 2016) no. 5, pages 277-289. Rigaud C, Barkaoui MA, Thomas C, et al.. Langerhans cell histiocytosis: therapeutic strategy and outcome in a 30-year References nationwide cohort of 1478 patients under 18 years of age. Chikwava K, Jaffe R. Langerin (CD207) staining in normal Br J Haematol. 2016; 174(6): 887-898. pediatric tissues, reactive lymph nodes, and childhood Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, et histiocytic disorders. Pediatr Dev Pathol. 2004 Nov- al.. The 2016 revision of the world health organization Dec;7(6):607-14 classification of lymphoid neoplasms. Blood, Emile JF, Abla O, Fraitag S, Horne A, Haroche J, Donadieu 2016,127(20):2375-2390 J, Requena-Caballero L, Jordan MB, Abdel-Wahab O, Allen CE, Charlotte F, Diamond EL, Egeler RM, Fischer A, This article should be referenced as such: Herrera JG, Henter JI, Janku F, Merad M, Picarsic J, Chen DB. Langerhans cell histiocytosis. Atlas Genet Rodriguez-Galindo C, Rollins BJ, Tazi A, Cytogenet Oncol Haematol. 2020; 24(3):146-151.

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