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Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia
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Edité par CCSD ; American Society of Hematology -
International audience. A half loss of RUNX1 activity leads to defects in primitive erythropoiesis, megakaryopoiesis, and proplatelet formation. • An almost complete loss of RUNX1 activity leads to the amplification of the granulomonocytic compartment with increased genomic instability. To explore how RUNX1 mutations predispose to leukemia, we generated induced plu-ripotent stem cells (iPSCs) from 2 pedigrees with germline RUNX1 mutations. The first, carrying a missense R174Q mutation, which acts as a dominant-negative mutant, is associated with thrombocytopenia and leukemia, and the second, carrying a monoallelic gene deletion inducing a haploinsufficiency, presents only as thrombocytopenia. Hema-topoietic differentiation of these iPSC clones demonstrated profound defects in eryth-ropoiesis and megakaryopoiesis and deregulated expression of RUNX1 targets. iPSC clones from patients with the R174Q mutation specifically generated an increased amount of granulomonocytes, a phenotype reproduced by an 80% RUNX1 knockdown in the H9 human embryonic stem cell line, and a genomic instability. This phenotype, found only with a lower dosage of RUNX1, may account for development of leukemia in patients. Altogether, RUNX1 dosage could explain the differential phenotype according to RUNX1 mutations, with a haploinsufficiency leading to thrombocytopenia alone in a majority of cases whereas a more complete gene deletion predisposes to leukemia.
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