Abstract
AbstractGiven 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.
Highlights
Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of immature progenitor cells, which are blocked from differentiating into normal blood cells
Megakaryoblastic leukemia of Down syndrome (ML-DS) is characterized by mutations in the hematopoietic transcription factor GATA1, which occur in fetal hematopoietic stem/progenitor cells (HSPCs) and cause the exclusive expression of an N-terminal truncated protein known as GATA1s, hereinafter referred to as GATA1s mutations.[3,4,5]
This finding was corroborated using an all-in-one vector system and is in line with our previous study showing that let-7c and miR-99a prevent the exhaustion of miR-125b transduced hematopoietic stem cells.[20] miR-125b further enhanced the Gata1s-induced expansion of CD1171 stem/progenitor cells, including CD1171CD411 megakaryocytic progenitors
Summary
Given the plasticity of hematopoietic stem and progenitor cells, multiple routes of differ-. MiR-125b–mediated repression of the megakaryocytic transcription factor ARID3A synergizes with GATA1s to induce leukemia. 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). 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. 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
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