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dc.contributor.authorAl-Kershi, Sina
dc.contributor.authorBhayadia, Raj
dc.contributor.authorNg, Michelle
dc.contributor.authorVerboon, Lonneke
dc.contributor.authorEmmrich, Stephan
dc.contributor.authorGack, Lucie
dc.contributor.authorSchwarzer, Adrian
dc.contributor.authorStrowig, Till
dc.contributor.authorHeckl, Dirk
dc.contributor.authorKlusmann, Jan-Henning
dc.date.accessioned2020-01-14T13:48:04Z
dc.date.available2020-01-14T13:48:04Z
dc.date.issued2019-12-23
dc.identifier.citationBlood Adv. 2019 Dec 23;3(24):4252-4263. doi: 10.1182/bloodadvances.2019032029.en_US
dc.identifier.issn2473-9537
dc.identifier.pmid31867596
dc.identifier.doi10.1182/bloodadvances.2019032029
dc.identifier.urihttp://hdl.handle.net/10033/622080
dc.description.abstractHOX genes are highly conserved, and their precisely controlled expression is crucial for normal hematopoiesis. Accordingly, deregulation of HOX genes can cause leukemia. However, despite of intensive research on the coding HOX genes, the role of the numerous long noncoding RNAs (lncRNAs) within the HOX clusters during hematopoiesis and their contribution to leukemogenesis are incompletely understood. Here, we show that the lncRNA HOXA10-AS, located antisense to HOXA10 and mir-196b in the HOXA cluster, is highly expressed in hematopoietic stem cells (HSCs) as well as in KMT2A-rearranged and NPM1 mutated acute myeloid leukemias (AMLs). Using short hairpin RNA- and locked nucleic acid-conjugated chimeric antisense oligonucleotide (LNA-GapmeR)-mediated HOXA10-AS-knockdown and CRISPR/Cas9-mediated excision in vitro, we demonstrate that HOXA10-AS acts as an oncogene in KMT2A-rearranged AML. Moreover, HOXA10-AS knockdown severely impairs the leukemic growth of KMT2A-rearranged patient-derived xenografts in vivo, while high HOXA10-AS expression can serve as a marker of poor prognosis in AML patients. Lentiviral expression of HOXA10-AS blocks normal monocytic differentiation of human CD34+ hematopoietic stem and progenitor cells. Mechanistically, we show that HOXA10-AS localizes in the cytoplasm and acts in trans to induce NF-κB target genes. In total, our data imply that the normally HSC-specific HOXA10-AS is an oncogenic lncRNA in KMT2A-r AML. Thus, it may also represent a potential therapeutic target in KMT2A-rearranged AML.en_US
dc.language.isoenen_US
dc.publisherAmerican Society of Haematologyen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleThe stem cell-specific long noncoding RNA HOXA10-AS in the pathogenesis of KMT2A-rearranged leukemia.en_US
dc.typeArticleen_US
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalBlood Advancesen_US
refterms.dateFOA2020-01-14T13:48:05Z
dc.source.journaltitleBlood advances


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