Skip to Main content Skip to Navigation
Journal articles

Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia

Abstract : 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.
Document type :
Journal articles
Complete list of metadata
Contributor : Ngere Ul Connect in order to contact the contributor
Submitted on : Thursday, January 11, 2018 - 1:54:48 PM
Last modification on : Friday, December 3, 2021 - 12:13:16 PM

Links full text



Iléana Antony-Debré, Vladimir Manchev, Nathalie Balayn, Dominique Bluteau, Cécile Tomowiak, et al.. Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia. Blood, American Society of Hematology, 2015, pp.930-940. ⟨10.1182/blood-2014-06-585513⟩. ⟨hal-01681166⟩



Record views