Level of RUNX1 Activity is Critical for Leukemic Predisposition but Not for Thrombocytopenia

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2014 Dec 11

PMID 25490895

Citations 45

Authors

Ileana Antony-Debre

Vladimir T Manchev

Nathalie Balayn

Dominique Bluteau

Cecile Tomowiak

Celine Legrand

Thierry Langlois

Olivia Bawa

Lucie Tosca

Gerard Tachdjian

Bruno Leheup

Najet Debili

Isabelle Plo

Jason A Mills

Deborah L French

Mitchell J Weiss

Eric Solary

Remi Favier

William Vainchenker

Hana Raslova

Affiliations

Soon will be listed here.

Abstract

To explore how RUNX1 mutations predispose to leukemia, we generated induced pluripotent 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. Hematopoietic differentiation of these iPSC clones demonstrated profound defects in erythropoiesis 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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