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The megakaryocytic transcription factor ARID3A suppresses leukemia pathogenesis
Given the plasticity of hematopoietic stem and progenitor cells, multiple routes of differentiation must be blocked in the the pathogenesis of acute myeloid leukemia, the molecular basis of which is incompletely understood. We report that posttranscriptional repression of the transcription factor AR...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Hematology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9632760/ https://www.ncbi.nlm.nih.gov/pubmed/34570885 http://dx.doi.org/10.1182/blood.2021012231 |
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author | Alejo-Valle, Oriol Weigert, Karoline Bhayadia, Raj Ng, Michelle Issa, Hasan Beyer, Christoph Emmrich, Stephan Schuschel, Konstantin Ihling, Christian Sinz, Andrea Zimmermann, Martin Wickenhauser, Claudia Flasinski, Marius Regenyi, Eniko Labuhn, Maurice Reinhardt, Dirk Yaspo, Marie-Laure Heckl, Dirk Klusmann, Jan-Henning |
author_facet | Alejo-Valle, Oriol Weigert, Karoline Bhayadia, Raj Ng, Michelle Issa, Hasan Beyer, Christoph Emmrich, Stephan Schuschel, Konstantin Ihling, Christian Sinz, Andrea Zimmermann, Martin Wickenhauser, Claudia Flasinski, Marius Regenyi, Eniko Labuhn, Maurice Reinhardt, Dirk Yaspo, Marie-Laure Heckl, Dirk Klusmann, Jan-Henning |
author_sort | Alejo-Valle, Oriol |
collection | PubMed |
description | Given the plasticity of hematopoietic stem and progenitor cells, multiple routes of differentiation must be blocked in the the pathogenesis of acute myeloid leukemia, the molecular basis of which is incompletely understood. We report that posttranscriptional repression of the transcription factor ARID3A by miR-125b is a key event in the pathogenesis of acute megakaryoblastic leukemia (AMKL). AMKL is frequently associated with trisomy 21 and GATA1 mutations (GATA1s), and children with Down syndrome are at a high risk of developing the disease. The results of our study showed that chromosome 21–encoded miR-125b synergizes with Gata1s to drive leukemogenesis in this context. Leveraging forward and reverse genetics, we uncovered Arid3a as the main miR-125b target behind this synergy. We demonstrated that, during normal hematopoiesis, this transcription factor promotes megakaryocytic differentiation in concert with GATA1 and mediates TGFβ-induced apoptosis and cell cycle arrest in complex with SMAD2/3. Although Gata1s mutations perturb erythroid differentiation and induce hyperproliferation of megakaryocytic progenitors, intact ARID3A expression assures their megakaryocytic differentiation and growth restriction. Upon knockdown, these tumor suppressive functions are revoked, causing a blockade of dual megakaryocytic/erythroid differentiation and subsequently of AMKL. Inversely, restoring ARID3A expression relieves the arrest of megakaryocytic differentiation in AMKL patient-derived xenografts. This work illustrates how mutations in lineage-determining transcription factors and perturbation of posttranscriptional gene regulation can interact to block multiple routes of hematopoietic differentiation and cause leukemia. In AMKL, surmounting this differentiation blockade through restoration of the tumor suppressor ARID3A represents a promising strategy for treating this lethal pediatric disease. |
format | Online Article Text |
id | pubmed-9632760 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society of Hematology |
record_format | MEDLINE/PubMed |
spelling | pubmed-96327602022-11-04 The megakaryocytic transcription factor ARID3A suppresses leukemia pathogenesis Alejo-Valle, Oriol Weigert, Karoline Bhayadia, Raj Ng, Michelle Issa, Hasan Beyer, Christoph Emmrich, Stephan Schuschel, Konstantin Ihling, Christian Sinz, Andrea Zimmermann, Martin Wickenhauser, Claudia Flasinski, Marius Regenyi, Eniko Labuhn, Maurice Reinhardt, Dirk Yaspo, Marie-Laure Heckl, Dirk Klusmann, Jan-Henning Blood Plenary Paper Given the plasticity of hematopoietic stem and progenitor cells, multiple routes of differentiation must be blocked in the the pathogenesis of acute myeloid leukemia, the molecular basis of which is incompletely understood. We report that posttranscriptional repression of the transcription factor ARID3A by miR-125b is a key event in the pathogenesis of acute megakaryoblastic leukemia (AMKL). AMKL is frequently associated with trisomy 21 and GATA1 mutations (GATA1s), and children with Down syndrome are at a high risk of developing the disease. The results of our study showed that chromosome 21–encoded miR-125b synergizes with Gata1s to drive leukemogenesis in this context. Leveraging forward and reverse genetics, we uncovered Arid3a as the main miR-125b target behind this synergy. We demonstrated that, during normal hematopoiesis, this transcription factor promotes megakaryocytic differentiation in concert with GATA1 and mediates TGFβ-induced apoptosis and cell cycle arrest in complex with SMAD2/3. Although Gata1s mutations perturb erythroid differentiation and induce hyperproliferation of megakaryocytic progenitors, intact ARID3A expression assures their megakaryocytic differentiation and growth restriction. Upon knockdown, these tumor suppressive functions are revoked, causing a blockade of dual megakaryocytic/erythroid differentiation and subsequently of AMKL. Inversely, restoring ARID3A expression relieves the arrest of megakaryocytic differentiation in AMKL patient-derived xenografts. This work illustrates how mutations in lineage-determining transcription factors and perturbation of posttranscriptional gene regulation can interact to block multiple routes of hematopoietic differentiation and cause leukemia. In AMKL, surmounting this differentiation blockade through restoration of the tumor suppressor ARID3A represents a promising strategy for treating this lethal pediatric disease. American Society of Hematology 2022-02-03 /pmc/articles/PMC9632760/ /pubmed/34570885 http://dx.doi.org/10.1182/blood.2021012231 Text en © 2022 by The American Society of Hematology This article is made available via the PMC Open Access Subset for unrestricted reuse and analyses in any form or by any means with acknowledgment of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections. |
spellingShingle | Plenary Paper Alejo-Valle, Oriol Weigert, Karoline Bhayadia, Raj Ng, Michelle Issa, Hasan Beyer, Christoph Emmrich, Stephan Schuschel, Konstantin Ihling, Christian Sinz, Andrea Zimmermann, Martin Wickenhauser, Claudia Flasinski, Marius Regenyi, Eniko Labuhn, Maurice Reinhardt, Dirk Yaspo, Marie-Laure Heckl, Dirk Klusmann, Jan-Henning The megakaryocytic transcription factor ARID3A suppresses leukemia pathogenesis |
title | The megakaryocytic transcription factor ARID3A suppresses leukemia
pathogenesis |
title_full | The megakaryocytic transcription factor ARID3A suppresses leukemia
pathogenesis |
title_fullStr | The megakaryocytic transcription factor ARID3A suppresses leukemia
pathogenesis |
title_full_unstemmed | The megakaryocytic transcription factor ARID3A suppresses leukemia
pathogenesis |
title_short | The megakaryocytic transcription factor ARID3A suppresses leukemia
pathogenesis |
title_sort | megakaryocytic transcription factor arid3a suppresses leukemia
pathogenesis |
topic | Plenary Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9632760/ https://www.ncbi.nlm.nih.gov/pubmed/34570885 http://dx.doi.org/10.1182/blood.2021012231 |
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