Long and Short Non-Coding Rnas As Regulators of Hematopoietic Differentiation
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Characterization of a Pediatric T-Cell Acute Lymphoblastic Leukemia Patient with Simultaneous LYL1 and LMO2 Rearrangements
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Erasmus University Digital Repository Articles and Brief Reports Acute Lymphoblastic Leukemia Characterization of a pediatric T-cell acute lymphoblastic leukemia patient with simultaneous LYL1 and LMO2 rearrangements Irene Homminga, 1 Maartje J. Vuerhard, 1 Anton W. Langerak, 2 Jessica Buijs-Gladdines, 1 Rob Pieters, 1 and Jules P.P. Meijerink 1 1Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children’s Hospital, Rotterdam; and 2Department of Immunology, Erasmus MC, Rotterdam, The Netherlands ABSTRACT Translocation of the LYL1 oncogene are rare in T-cell acute consistently clustered along with cases having TAL1 or lymphoblastic leukemia, whereas the homologous TAL1 LMO2 rearrangements. Therefore, LYL1 -rearranged cases are gene is rearranged in approximately 20% of patients. not necessarily associated with immature T-cell develop - Previous gene-expression studies have identified an imma - ment, despite high LYL1 levels, but elicit a TALLMO expres - ture T-cell acute lymphoblastic leukemia subgroup with high sion signature. LYL1 expression in the absence of chromosomal aberrations. Molecular characterization of a t(7;19)(q34;p13) in a pediatric Key words: T-ALL, pediatric, LYL1, LMO2, rearrangements. T-cell acute lymphoblastic leukemia patient led to the identi - fication of a translocation between the TRB@ and LYL1 loci. Citation: Homminga I, Vuerhard MJ, Langerak AW, Buijs- Similar to incidental T-cell acute lymphoblastic leukemia Gladdines J, Pieters R, and Meijerink JPP. Characterization of a cases with synergistic, double translocations affecting pediatric T-cell acute lymphoblastic leukemia patient with simul - TAL1/2 and LMO1/2 oncogenes, this LYL1 -translocated taneous LYL1 and LMO2 rearrangements. -
Homeobox Gene Methylation in Lung Cancer Studied by Genome-Wide Analysis with a Microarray-Based Methylated Cpg Island Recovery Assay
Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay Tibor Rauch*, Zunde Wang*, Xinmin Zhang†, Xueyan Zhong*, Xiwei Wu‡, Sean K. Lau§, Kemp H. Kernstine¶, Arthur D. Riggs*ʈ, and Gerd P. Pfeifer*ʈ *Division of Biology, ‡Division of Information Sciences, §Division of Pathology, and ¶Division of Surgery, Beckman Research Institute of the City of Hope, Duarte, CA 91010; and †NimbleGen Systems, Inc., Madison, WI 53711 Contributed by Arthur D. Riggs, February 5, 2007 (sent for review December 11, 2006) De novo methylation of CpG islands is a common phenomenon in and in this way they are key determinants of cell identity and human cancer, but the mechanisms of cancer-associated DNA potential targets during tumorigenesis. methylation are not known. We have used tiling arrays in combi- We recently developed a DNA methylation detection technique, nation with the methylated CpG island recovery assay to investi- the methylated CpG island recovery assay (MIRA) (12). This gate methylation of CpG islands genome-wide and at high reso- technique is based on the high affinity of a complex of the MBD2b lution. We find that all four HOX gene clusters on chromosomes 2, and MBD3L1 proteins for CpG-methylated DNA (13) and is 7, 12, and 17 are preferential targets for DNA methylation in cancer compatible with microarray-based methodology (14). We previ- cell lines and in early-stage lung cancer. CpG islands associated ously found that several homeobox genes were methylated in a lung with many other homeobox genes, such as SIX, LHX, PAX, DLX, and cancer cell line (14). -
Continuous MLL-ENL Expression Is Necessary to Establish a ''Hox Code'' and Maintain Immortalization of Hematopoietic Progenitor Cells
Research Article Continuous MLL-ENL Expression Is Necessary to Establish a ‘‘Hox Code’’ and Maintain Immortalization of Hematopoietic Progenitor Cells Sarah J. Horton,1 David G. Grier,3 Glenda J. McGonigle,3 Alexander Thompson,3 Michelle Morrow,1 Inusha De Silva,1 Dale A. Moulding,1 Dimitris Kioussis,2 Terence R.J. Lappin,3 Hugh J.M. Brady,1 and Owen Williams1 1Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London; 2Division of Molecular Immunology, National Institute for Medical Research, London, United Kingdom; and 3Department of Child Health, Queen’s University, Belfast, United Kingdom Abstract essential for definitive hematopoiesis and that it is required to The t[(11;19)(p22;q23)] translocation, which gives rise to the maintain, but not to initiate, the expression of multiple Hox genes MLL-ENL fusion protein, is commonly found in infant acute during embryogenesis (5–9). Some Hox genes are oncogenic when leukemias of both the myeloid and lymphoid lineage. To overexpressed in hematopoietic progenitor cells (10, 11). Taken investigate the molecular mechanism of immortalization by together, this suggests that aberrant regulation of Hox genes by MLL-ENL we established a Tet-regulatable system of MLL- MLL fusion proteins is the basis for leukemias involving MLL ENL expression in primary hematopoietic progenitor cells. translocations (12). Several recent publications do indeed suggest Immortalized myeloid cell lines were generated, which that Hox genes may play an important role in leukemia induced by are dependent on continued MLL-ENL expression for their MLL fusion proteins (13–16). survival and proliferation. These cells either terminally MLL translocations result in the generation of an in-frame differentiate or die when MLL-ENL expression is turned chimeric fusion in which MLL is joined to one of over 40 different off with doxycycline. -
The Role of Noncoding Mutations in Blood Cancers Sunniyat Rahman and Marc R
© 2019. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2019) 12, dmm041988. doi:10.1242/dmm.041988 REVIEW The role of noncoding mutations in blood cancers Sunniyat Rahman and Marc R. Mansour* ABSTRACT survival in adult acute myeloid leukaemia (AML) and ALL are The search for oncogenic mutations in haematological malignancies still less than 50%, with significant treatment challenges including has largely focused on coding sequence variants. These variants treatment-resistant disease, clonal heterogeneity of the underlying have been critical in understanding these complex cancers in greater disease, treatment-associated toxicities and poor tolerance for detail, ultimately leading to better disease monitoring, subtyping and intensive treatment regimens, particularly in older patients with prognostication. In contrast, the search for oncogenic variants in the comorbidities (Kansagra et al., 2018). Because of this, there is a noncoding genome has proven to be challenging given the vastness significant impetus to discover new genetic aberrations, including of the search space, the intrinsic difficulty in assessing the impact of driver mutations (see Box 1 for a glossary of terms), that may variants that do not code for functional proteins, and our still primitive provide insight into the mechanisms of malignant haematopoiesis, understanding of the function harboured by large parts of the as well as offering novel therapeutic opportunities. noncoding genome. Recent studies have broken ground on this Detailed genetic characterisation of haematological malignancies quest, identifying somatically acquired and recurrent mutations in the has already identified alterations that are now being used for better noncoding genome that activate the expression of proto-oncogenes. diagnosis, prognostication, subtype identification and to inform In this Review, we explore some of the best-characterised examples therapeutic decisions (Taylor et al., 2017). -
Rabbit Anti-HOXA6/FITC Conjugated Antibody
SunLong Biotech Co.,LTD Tel: 0086-571- 56623320 Fax:0086-571- 56623318 E-mail:[email protected] www.sunlongbiotech.com Rabbit Anti-HOXA6/FITC Conjugated antibody SL11294R-FITC Product Name: Anti-HOXA6/FITC Chinese Name: FITC标记的同源盒基因HOXA6蛋白抗体 HOX1B; Homeo box 1B; Homeo box A6; Homeobox 1B; Homeobox A6; Homeobox protein Hox A6; Homeobox protein Hox-1B; Homeobox protein Hox-A6 antibody Alias: Homeobox protein HoxA6; HOX 1; Hox 1B; HOX1; HOX1.2; Hox1B; HOXA6; HX A6; HXA6; HXA6_HUMAN. Organism Species: Rabbit Clonality: Polyclonal React Species: Human,Mouse,Rat,Dog,Pig,Horse,Sheep, ICC=1:50-200IF=1:50-200 Applications: not yet tested in other applications. optimal dilutions/concentrations should be determined by the end user. Molecular weight: 23kDa Form: Lyophilized or Liquid Concentration: 1mg/ml immunogen: KLH conjugated synthetic peptide derived from human HOXA6/HOX1B (171-233aa) Lsotype: IgG Purification: affinitywww.sunlongbiotech.com purified by Protein A Storage Buffer: 0.01M TBS(pH7.4) with 1% BSA, 0.03% Proclin300 and 50% Glycerol. Store at -20 °C for one year. Avoid repeated freeze/thaw cycles. The lyophilized antibody is stable at room temperature for at least one month and for greater than a year Storage: when kept at -20°C. When reconstituted in sterile pH 7.4 0.01M PBS or diluent of antibody the antibody is stable for at least two weeks at 2-4 °C. background: The Hox homeobox genes encode proteins that are transcriptional regulators with an established role in embryonic development. HoxA6 (homeobox A6), also known as Product Detail: HOX1B, is a 233 amino acid protein that localizes to the nucleus. -
LMO T-Cell Translocation Oncogenes Typify Genes Activated by Chromosomal Translocations That Alter Transcription and Developmental Processes
Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE LMO T-cell translocation oncogenes typify genes activated by chromosomal translocations that alter transcription and developmental processes Terence H. Rabbitts1 Medical Research Council (MRC) Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Cambridge CB2 2QH, UK The cytogenetic analysis of tumors, particularly those of ment (immunoglobulin or T-cell receptor) occurs and oc- hematopoietic origin, has revealed that reciprocal chro- casionally mediates chromosomal translocation. This mosomal translocations are recurring features of these type of translocation causes oncogene activation result- tumors. Further from the initial recognition of the trans- ing from the new chromosomal environment of the re- location t(9;22) (Nowell and Hungerford 1960; Rowley arranged gene. In general, this means inappropriate gene 1973), it has become clear that particular chromosomal expression. The second, and probably the most common translocations are found consistently in specific tumor outcome of chromosomal translocations, is gene fusion subtypes. A principle example of this is the translocation in which exons from a gene on each of the involved chro- t(8;14)(q24;q32.1) invariably found in the human B cell mosomes are linked after the chromosomal transloca- tumor Burkitt’s lymphoma (Manolov and Manolov 1972; tion, resulting in a fusion mRNA and protein. This type Zech et al. 1976). The link with the immunoglobulin of event is found in many cases of hematopoietic tumors H-chain locus on chromosome 14, band q32.1 (Croce et and in the sarcomas. al. 1979; Hobart et al. -
A Previously Unrecognized Promoter of LMO2 Forms Part of A
Oncogene (2010) 29, 5796–5808 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc ORIGINAL ARTICLE A previously unrecognized promoter of LMO2 forms part of a transcriptional regulatory circuit mediating LMO2 expression in a subset of T-acute lymphoblastic leukaemia patients SH Oram1, JAI Thoms2, C Pridans1, ME Janes2, SJ Kinston1, S Anand1, J-R Landry3, RB Lock4, P-S Jayaraman5, BJ Huntly1, JE Pimanda2 and B Go¨ttgens1 1Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK; 2Lowy Cancer Research Centre and The Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia; 3Institute for Research in Immunology and Cancer, Universite´ de Montre´al, Montre´al, Quebec, Canada; 4Children’s Cancer Institute Australia, University of New South Wales, Sydney, New South Wales, Australia and 5Birmingham University Stem Cell Centre, University of Birmingham, Edgbaston, Birmingham, UK The T-cell oncogene Lim-only 2 (LMO2) critically Introduction influences both normal and malignant haematopoiesis. LMO2 is not normally expressed in T cells, yet ectopic Lim-only 2 (LMO2), also known as TTG2 or RBTN2, expression is seen in the majority of T-acute lympho- was originally reported as a T-cell oncogene where it blastic leukaemia (T-ALL) patients with specific translo- was recurrently rearranged by chromosomal transloca- cations involving LMO2 in only a subset of these patients. tion in T-cell malignancies (Boehm et al., 1991; Royer- Ectopic lmo2 expression in thymocytes of transgenic mice Pokora et al., 1991). LMO2 encodes a 156 amino-acid causes T-ALL, and retroviral vector integration into the transcriptional co-factor containing two LIM domain LMO2 locus was implicated in the development of clonal zinc-fingers (Kadrmas and Beckerle, 2004) that do not T-cell disease in patients undergoing gene therapy. -
Letters to the Editor
LETTERS TO THE EDITOR The significant upregulation of Gata1 and EpoR mRNA Mice over-expressing human erythropoietin expression in hEPO over-expressing tg6 mice was con - indicate that erythropoietin enhances expression firmed by analyzing the spleen as a major source of of its receptor via up-regulated Gata1 and Tal1 hematopoiesis (Figure 2A and B). To further dissect the complexity of changes in the transcriptional network, the analysis of Myb mRNA expression served as marker for The development of medullary hematopoiesis is char - adult definitive erythroblasts, 10 showing significantly acterized by a specific expression profile of hematopoiet - ic transcription factors, including GATA transcription fac - tors. At mid-gestation, when hematopoiesis is newly A GATA 1 2 established in the bone marrow of human fetuses, initial - wt ly high GATA2 expression becomes subsequently down- regulated, while GATA1 expression increases in parallel. 1 1.5 Both transcription factors bind to overlapping sets of tg6 hematopoietic downstream target genes, often at distinct 1 sites, to regulate the balance between proliferation and differentiation. Chromatin occupancy by GATA1 and 0.5 GATA2 can change in the course of hematopoietic differ - entiation, leading to the so-called GATA switch. 2 Thus, a 0 n d7 d21 d49 i spatio-temporal regulation of GATA1 or GATA2 activities t c is required within lineage-specific differentiation. During a - erythroid differentiation GATA1 expression peaks at the b B GATA 2 3 o level of colony-forming units (CFU-E), where erythro - t 2 e poietin (Epo) exerts most specifically its effects, but v i t blocks terminal maturation if constitutively over- a 1.5 l 4 e expressed. -
Rahman Et Al 2017 Somatically Acquired Activation of LMO2 in T-ALL
Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Rahman, Sunniyat, Michael Magnussen, Theresa E. León, Nadine Farah, Zhaodong Li, Brian J. Abraham, Krisztina Z. Alapi, et al. “Activation of the LMO2 Oncogene through a Somatically Acquired Neomorphic Promoter in T-Cell Acute Lymphoblastic Leukemia.” Blood 129, no. 24 (March 7, 2017): 3221–3226. As Published https://doi.org/10.1182/blood-2016-09-742148 Publisher American Society of Hematology Version Author's final manuscript Citable link http://hdl.handle.net/1721.1/117283 Terms of Use Creative Commons Attribution-Noncommercial-Share Alike Detailed Terms http://creativecommons.org/licenses/by-nc-sa/4.0/ 1 Activation of the LMO2 oncogene through a somatically acquired 2 neomorphic promoter in T-Cell Acute Lymphoblastic Leukemia 3 4 Sunniyat Rahman1, Michael Magnussen1, Theresa E. León1, Nadine Farah1, Zhaodong Li2, 5 Brian J Abraham3, Krisztina Z. Alapi1, Rachel J. Mitchell1, Tom Naughton1, Adele K. 6 Fielding1, Arnold Pizzey1, Sophia Bustraan1, Christopher Allen1, Teodora Popa , Karin Pike- 7 Overzet5, Laura Garcia-Perez5, Rosemary E. Gale1, David C. Linch1, Frank J.T. Staal5, 8 Richard A. Young3,4, A. Thomas Look2,6, Marc R. Mansour1 9 10 1. University College London Cancer Institute, Department of Haematology, 72 Huntley 11 Street, London. WC1E 6DD. United Kingdom. 12 2. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical 13 School, Boston, MA 02215 14 3. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 15 02142 16 4. -
Kobe University Repository : Thesis
Kobe University Repository : Thesis Afadin Regulates Puncta Adherentia Junction Formation and 学位論文題目 Presynaptic Differentiation in Hippocampal Neurons(アファディンは海 Title 馬ニューロンにおいてアドへレンスジャンクションの形成と前シナプ スの分化を調節している) 氏名 Toyoshima, Daisaku Author 専攻分野 博士(医学) Degree 学位授与の日付 2014-03-25 Date of Degree 公開日 2015-03-01 Date of Publication 資源タイプ Thesis or Dissertation / 学位論文 Resource Type 報告番号 甲第6188号 Report Number 権利 Rights JaLCDOI URL http://www.lib.kobe-u.ac.jp/handle_kernel/D1006188 ※当コンテンツは神戸大学の学術成果です。無断複製・不正使用等を禁じます。著作権法で認められている範囲内で、適切にご利用ください。 PDF issue: 2021-09-26 Afadin Regulates Puncta Adherentia Junction Formation and Presynaptic Differentiation in Hippocampal Neurons アファディンは海馬ニューロンにおいてアドへレンスジャンクション の形成と前シナプスの分化を調節している 豊嶋大作, 萬代研二, 丸尾知彦、Irwan Supriyanto、 富樫英、井上貴仁、森正弘、高井義美 神戸大学大学院医学研究科医科学専攻 小児科学 (指導教員:飯島一誠 教授) 豊嶋大作 Key words: Afadin, puncta adherentia junction, presynapse, hippocampal neuron Manuscript Click here to download Manuscript: Toyoshima_text_revised_2nd_final.pdf 1 Afadin Regulates Puncta Adherentia Junction Formation and 2 Presynaptic Differentiation in Hippocampal Neurons 3 4 Daisaku Toyoshima1,3,4, Kenji Mandai1,3, Tomohiko Maruo1,3, Irwan Supriyanto2,3, 5 Hideru Togashi1,3, Takahito Inoue1,3, Masahiro Mori2,3 & Yoshimi Takai1,3 6 7 1. Department of Biochemistry and Molecular Biology, Kobe University Graduate 8 School of Medicine, Kobe, Hyogo 650-0047, Japan. 9 2. Faculty of Health Sciences, Kobe University Graduate School of Health Sciences, 10 Kobe, Hyogo 654-0142, Japan. 11 3. CREST, Japan Science and Technology Agency, Kobe, Hyogo 650-0047, Japan. 12 4. Present address: Department of Pediatrics, Kobe University Graduate School of 13 Medicine, Kobe, Hyogo 650-0017, Japan. 14 15 Correspondence should be addressed to Y.T. ([email protected]), K.M. 16 ([email protected]). -
T-Cell Lymphoblastic Lymphoma Arising in the Setting of Myeloid/Lymphoid Neoplasms with Eosinophilia
cancers Article T-Cell Lymphoblastic Lymphoma Arising in the Setting of Myeloid/Lymphoid Neoplasms with Eosinophilia: LMO2 Immunohistochemistry as a Potentially Useful Diagnostic Marker Magda Zanelli 1 , Giuseppe G. Loscocco 2,3 , Elena Sabattini 4, Maurizio Zizzo 5,6,* , Francesca Sanguedolce 7, Luigi Panico 8, Daniela Fanni 9, Raffaella Santi 10, Cecilia Caprera 11, Cristiana Rossi 12, Alessandra Soriano 13,14, Alberto Cavazza 1, Alessandro Giunta 5, Cristina Mecucci 15, Alessandro M. Vannucchi 2,3, Stefano A. Pileri 16 and Stefano Ascani 11,15 1 Pathology Unit, Azienda Unità Sanitaria Locale—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; [email protected] (M.Z.); [email protected] (A.C.) 2 Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; gloscocco@unifi.it (G.G.L.); a.vannucchi@unifi.it (A.M.V.) 3 Center of Research and Innovation of Myeloproliferative Neoplasms (CRIMM), Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy 4 Citation: Zanelli, M.; Loscocco, G.G.; Haematopathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; Sabattini, E.; Zizzo, M.; [email protected] 5 Sanguedolce, F.; Panico, L.; Fanni, D.; Surgical Oncology Unit, Azienda Unità Sanitaria Locale—IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy; [email protected] Santi, R.; Caprera, C.; Rossi, C.; et al. 6 Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, T-Cell Lymphoblastic Lymphoma 41121 Modena, Italy Arising in the Setting of 7 Pathology Unit, Azienda Ospedaliero-Universitaria—Ospedali Riuniti di Foggia, 71122 Foggia, Italy; Myeloid/Lymphoid Neoplasms with [email protected] Eosinophilia: LMO2 8 Pathology Unit Azienda Ospedaliera dei Colli Monaldi-Cotugno-CTO, P.O. -
Inactivation of HOXA Genes by Hypermethylation in Myeloid and Lymphoid Malignancy Is Frequent and Associated with Poor Prognosis Gordon Strathdee,1Tessa L
Imaging, Diagnosis, Prognosis Inactivation of HOXA Genes by Hypermethylation in Myeloid and Lymphoid Malignancy is Frequent and Associated with Poor Prognosis Gordon Strathdee,1Tessa L. Holyoake,2 Alyson Sim,1Anton Parker,4 David G. Oscier,4 Junia V. Melo, 5 Stefan Meyer,6,7 Tim Eden,7 Anne M. Dickinson,8 Joanne C. Mountford,2 Heather G. Jorgensen,2 Richard Soutar, 3 and Robert Brown1 Abstract Purpose: The HOX genes comprise a large family of homeodomain-containing transcription factors, present in four separate clusters, which are key regulators of embryonic development, hematopoietic differentiation, and leukemogenesis. We aimed to study the role of DNA methyl- ation as an inducer of HOX gene silencing in leukemia. Experimental Design: Three hundred and seventy-eight samples of myeloid and lymphoid leukemia were quantitatively analyzed (by COBRA analysis and pyrosequencing of bisulfite- modified DNA) for methylation of eight HOXA and HOXB cluster genes. The biological significance of the methylation identified was studied by expression analysis and through re-expression of HOXA5 in a chronic myeloid leukemia (CML) blast crisis cell line model. Results: Here, we identify frequent hypermethylation and gene inactivation of HOXA and HOXB cluster genes in leukemia. In particular, hypermethylation of HOXA4 and HOXA5 was frequently observed (26-79%) in all types of leukemias studied. HOXA6 hypermethylation was predomi- nantly restricted to lymphoid malignancies, whereas hypermethylation of other HOXA and HOXB genes was only observed in childhood leukemia. HOX gene methylation exhibited clear correla- tions with important clinical variables, most notably in CML, in which hypermethylation of both HOXA5 (P = 0.00002) and HOXA4 (P = 0.006) was strongly correlated with progression to blast crisis.