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Microrna-155-5P Plays a Critical Role in Transient Leukemia of Down Syndrome by Targeting Tumor Necrosis Factor Receptor Superfamily Members

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Microrna-155-5P Plays a Critical Role in Transient Leukemia of Down Syndrome by Targeting Tumor Necrosis Factor Receptor Superfamily Members Cellular Physiology Cell Physiol Biochem 2020;54:994-1012 DOI: 10.33594/00000028310.33594/000000283 © 2020 The Author(s).© 2020 Published The Author(s) by and Biochemistry Published online: online: 3 3October October 2020 2020 Cell Physiol BiochemPublished Press GmbH&Co. by Cell Physiol KG Biochem 994 Press GmbH&Co. KG, Duesseldorf SasAccepted: et al.: 10 miR-155-5p September 2020 Targeting TNF-Alpha Leads www.cellphysiolbiochem.comto Transient Leukemia in Down SyndromeThis article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 Interna- tional License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Original Paper MicroRNA-155-5p Plays a Critical Role in Transient Leukemia of Down Syndrome by Targeting Tumor Necrosis Factor Receptor Superfamily Members Valentina Sasa,b Sergiu Pascac Ancuta Jurjd Laura Popd Hideki Muramatsue Hiroko Onoe Delia Dimaf Patric Teodorescua Sabina Ilutaa Cristina Turcasa Anca Onaciuc Raluca Munteanuc Alina-Andreea Zimtac Cristina Blagb,g Gheorghe Popab,g Elias Daniel Alexander von Gamma Smaranda Arghirescuh,i Margit Serbanh,i Sorin Manb Mirela Marianf Bobe Petrushevc Cristian Bercec Anca Colitaj,k Mihnea Zdrengheaa,f Seiji Kojimae Diana Guleia,c Yoshiyuki Takahashie Ciprian Tomuleasaa,c,f aDepartment of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca, Cluj Napoca, Romania, bDepartment of Pediatrics, Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca, Cluj Napoca, Romania, cMedfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca, Cluj Napoca, Romania, dResearch Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca, Cluj Napoca, Romania, eDepartment of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan, fDepartment of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj Napoca, Romania, gDepartment of Pediatrics, Emergency Hospital for Children in Cluj Napoca, Cluj Napoca, Romania, hDepartment of Pediatrics, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania, iDepartment of Pediatrics, Louis Turcanu Emergency Hospital for Children, Timisoara, Romania, jDepartment of Pediatrics, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania, kDepartment of Pediatrics, Fundeni Clinical Institute, Bucharest, Romania Key Words miR-155 • TNF-alpha • Down syndrome • Leukemia Abstract Background/Aims: Down syndrome associated disorders are caused by a complex genetic context where trisomy 21 is a central component in relation to other changes involving epi- genetic regulators and signaling molecules. This unique genetic context is responsible for the predisposition of people with Down syndrome to acute leukemia. Although, the research in V. Sas, S. Pasca and A. Jurj contributed equally to the current manuscript and all three are considered to be first authors. Ciprian Tomuleasa, M.D. Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Gheorghe Marinescu Street, Cluj Napoca, 400124 (Romania) E-Mail [email protected] Cellular Physiology Cell Physiol Biochem 2020;54:994-1012 DOI: 10.33594/000000283 © 2020 The Author(s). Published by and Biochemistry Published online: 3 October 2020 Cell Physiol Biochem Press GmbH&Co. KG 995 Sas et al.: miR-155-5p Targeting TNF-Alpha Leads to Transient Leukemia in Down Syndrome this field has discovered some important pathogenic keys, the exact mechanism of this pre- disposition is not known. Methods: In this study we applied functional enrichment analysis to evaluate the interactions between genes localized on chromosome 21, genes already identify as having a key role in acute leukemia of Down syndrome, miRNAs and signaling pathways implicated in cancer and cell development and found that miR-155 has a high impact in genes present on chromosome 21. Forward, we performed next generation sequencing on DNA samples from a cohort of patients diagnosed with acute leukemia of Down syndrome and in vitro functional assay using a CMK-86 cell line, transfected with either mimic or inhibitor of the microRNA-155-5p. Results: Our results show that the epigenetic alteration of the TNF superfamily receptors in Down syndrome, which can be correlated to microRNA-155-5p aber- rant activity, may play an important role in cell signaling and thus be linked to acute myeloid leukemia. Conclusion: Some genes, already shown to be mutated in AML-DS, are potential targets for miR-155. Our results show that the epigenetic alteration of the TNF superfamily receptors in Down syndrome may play an important role in cell signaling and thus be linked to acute myeloid leukemia. © 2020 The Author(s). Published by Cell Physiol Biochem Press GmbH&Co. KG Introduction Discovered by John Langdon Down in 1866 [1], Down syndrome (DS) continues to be the most frequent chromosomal disorder of the Western world [2]. Besides the clinical, well known, characteristics of DS, hematological disorders are important features and can be re- sponsible for a unique pathological context. Persons with DS may present with macrocytosis, transient platelet count abnormalities and transient leukemia of Down syndrome (TL-DS), and have a 10–20 fold increased risk of acute myeloblastic (AML-DS) and acute lymphoblas- tic (ALL-DS) leukemias [3, 4], indicating the crucial role played by trisomy 21 in hematopoi- esis [5–10]. Morbidity and mortality caused by solid tumors is less frequent in DS patients [11, 12]. A unique hematological feature of Down syndrome is the presence of TL-DS in 4-10% of DS neonates [13–15], with a spontaneous resolution in most of the cases [13]. The World blast cells in neonates with DS [16]. Tunstall et al. recommend that TL-DS should be de- Health Organization (WHO) defines transient leukemia of DS as increased peripheral blood >10% and/or clinical features suggestive of TL-DS in a child with DS or mosaic trisomy 21 [17].fined Basedas the presenceon clinical of anda GATA1 hematological mutation togetheraspects, withthe prevalence a peripheral of blood TL-DS blast is estimated percentage at 5-10% [15], but the true incidence of TL-DS is hard to estimate because of asymptomatic cases, intrauterine deaths, stillborn cases and the possibility of resolution prior to birth [18]. The diagnosis of TL-DS is important because it can progress to AML-DS [19]. 20-30% in TL-DS are indistinguishable from true leukemic cells in both morphology and expressed surfaceof TL-DS markers cases will [22]. develop The true acute mechanism leukemia of in progression the first 3 years from of TL-DS life [14, to AML-DS 20, 21]. inThe not blasts fully - codingunderstood, members but research of cohesin in thisprotein field family, showed epigenetic that AML-DS regulators, clonally and evolves signaling from moleculesTL-DS, by [23–26].persistent GATA1 mutant cells acquiring additional mutations, most frequently in genes en predominant form of leukemia in DS children under age 4, ALL-DS dominating in older chil- drenWHO [22]. 20%classification of leukemia of leukemias associated recognizes with DS, without AML-DS counting as a separate TL-DS entity cases, [11], is acute being mega the- karyoblastic leukemia (AMkL-DS) [14]. Together with myelodysplastic syndrome (MDS), its incidence is approximately 500 times more common in DS than in normal children [27]. AMkL-DS originated from one of the multiple subclones present in the TL-DS phase with a haveshared an GATA1 increased mutation sensitivity [23]. toAMkL-DS cytosine has arabinoside unique characteristics, secondary to increasedbeside the expression preleukemic of state, unusual chromosomal findings, it shows a high cure rate [14]. Patients with AMkL-DS Cellular Physiology Cell Physiol Biochem 2020;54:994-1012 DOI: 10.33594/000000283 © 2020 The Author(s). Published by and Biochemistry Published online: 3 October 2020 Cell Physiol Biochem Press GmbH&Co. KG 996 Sas et al.: miR-155-5p Targeting TNF-Alpha Leads to Transient Leukemia in Down Syndrome the chromosome 21-localized gene, cystathionine-b-synthase, and potentially global mecha- nisms which increase the susceptibility of cells to undergo apoptosis and should be treated according to a less intensive protocol [28, 29]. In the current manuscript we describe the epigenetic events linked to AML-DS, by iden- tifying microRNA-155-5p as a key molecular player in leukemia progression, as well as its potential targets. Materials and Methods Functional enrichment analysis and miRNAs targets We evaluated the interactions between genes localized on chromosome 21, genes already identify as having a key role in AML-DS, miRNAs and signaling pathways implicated in cancer and cell development. - base.Genes present on chromosome 21 from: http://atlasgeneticsoncology.org/Indexbychrom/idxg_21.html. On these we applied STRING software and did functional enrichment analysis using R 3.5.3 and the GO data faces/upload/MirUploadView.xhtml) and analyzed which of them are implicated in processes in the bone marrow.After After this this we we introduced selected the all pathwaysmicroRNAs considered from chromosome of interest to21 us in and miRNet had a (https://www.mirnet.ca/p Because of the high number of genes targeted by hsa-miR-155-5p and its known<0.05 implications using KEGG in cancer as the indatabase: general, pathways we chose in to cancer, continue acute using myeloid only the leukemia, genes that p53 were signaling targeted pathway by hsa-miR-155-5p and cell cycle. and that were deregulated in the pathways selected. On these genes we also applied functional enrichment analysis us- anding R PANTHER 3.5.3 and pathways the GO database. [32]. Further, Considering we used the R data3.5.3 obtained and the packageby Labuhn multiMIR et al., we and selected considered the 18 a targetgenes studied [26], plus GATA1 in STRING; enrichment analysis was performed using KEGG [30], Reactome [31] valid Nextif it was generation present sequencingin one of the on following DNA samples validated from datasets: a cohort miRecords, of patients miRTarBasediagnosed with and TL-DSTarBase and [33].
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