The megakaryocytic transcription factor ARID3A suppresses leukemia pathogenesis
The megakaryocytic transcription factor ARID3A suppresses leukemia pathogenesis
Abstract Given the plasticity of hematopoietic stem/progenitor cells, multiple routes of differentiation must be blocked during acute myeloid leukemia pathogenesis – the molecular basis of which is incompletely understood. Here we report that post-transcriptional repression of transcription factor ARID3A by miR-125b is a key event in megakaryoblastic leukemia (AMKL) pathogenesis. AMKL is frequently associated with trisomy 21 and GATA1 mutations (GATA1s), and children with Down syndrome are at a high risk of developing this disease. We show that chromosome 21-encoded miR-125b synergizes with Gata1s to drive leukemogenesis in this context. Leveraging forward and reverse genetics, we uncover Arid3a as the main miR-125b target underlying this synergy. We demonstrate 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. While 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 dual megakaryocytic/erythroid differentiation blockade and subsequently AMKL. Inversely, restoring ARID3A expression relieves the megakaryocytic differentiation arrest in AMKL patient-derived xenografts. This work illustrates how mutations in lineage-determining transcription factors and perturbation of post-transcriptional gene regulation interplay to block multiple routes of hematopoietic differentiation and cause leukemia. Surmounting this differentiation blockade in megakaryoblastic leukemia by restoring the tumor suppressor ARID3A represents a promising strategy for treating this lethal pediatric disease. Key pointsRepression of megakaryocytic transcription factor ARID3A by miR-125b synergizes with GATA1s to induce leukemiaRestoring ARID3A expression relieves megakaryocytic differentiation arrest in megakaryoblastic leukemia Graphical abstractbiorxiv;2021.04.26.440795v1/UFIG1F1ufig1
Reinhardt Dirk、Yaspo Marie-Laure、Ng Michelle、Schuschel Konstantin、Ihling Christian、Flasinski Marius、Klusmann Jan-Henning、Regenyi Eniko、Emmrich Stephan、Sinz Andrea、Weigert Karoline、Labuhn Maurice、Alejo-Valle Oriol、Bhayadia Raj、Heckl Dirk、Issa Hasan、Beyer Christoph
Pediatric Hematology and Oncology, Pediatrics III, University Hospital EssenMax Planck Institute for Molecular GeneticsPediatric Hematology and Oncology, Martin-Luther-University Halle-WittenbergPediatric Hematology and Oncology, Martin-Luther-University Halle-WittenbergDepartment of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin-Luther-University Halle-WittenbergDepartment of Psychiatry, Psychosomatic Medicine and PsychotherapyPediatric Hematology and Oncology, Martin-Luther-University Halle-WittenbergPediatric Hematology and Oncology, Martin-Luther-University Halle-Wittenberg||Max Planck Institute for Molecular GeneticsDepartment of Biology, University of RochesterDepartment of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin-Luther-University Halle-WittenbergPediatric Hematology and Oncology, Martin-Luther-University Halle-WittenbergInstitute for Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection ResearchPediatric Hematology and Oncology, Martin-Luther-University Halle-WittenbergPediatric Hematology and Oncology, Martin-Luther-University Halle-WittenbergPediatric Hematology and Oncology, Martin-Luther-University Halle-WittenbergPediatric Hematology and Oncology, Martin-Luther-University Halle-WittenbergPediatric Hematology and Oncology, Martin-Luther-University Halle-Wittenberg
基础医学肿瘤学分子生物学
Acute myeloid leukemiaDown syndromemiR-125ARID3AGATA1
Reinhardt Dirk,Yaspo Marie-Laure,Ng Michelle,Schuschel Konstantin,Ihling Christian,Flasinski Marius,Klusmann Jan-Henning,Regenyi Eniko,Emmrich Stephan,Sinz Andrea,Weigert Karoline,Labuhn Maurice,Alejo-Valle Oriol,Bhayadia Raj,Heckl Dirk,Issa Hasan,Beyer Christoph.The megakaryocytic transcription factor ARID3A suppresses leukemia pathogenesis[EB/OL].(2025-03-28)[2025-04-28].https://www.biorxiv.org/content/10.1101/2021.04.26.440795.点此复制
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