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

Iléana Antony-Debré (1, 2, 3, 4) , Vladimir T Manchev (1, 3, 5) , Nathalie Balayn (1, 5) , Dominique Bluteau (1, 5, 6) , Cécile Tomowiak (1, 7) , Céline Legrand (1, 5) , Thierry Langlois (1, 5) , Olivia Bawa (8) , Lucie Tosca (9, 10) , Gérard Tachdjian (9, 10) , Bruno Leheup (11, 12) , Najet Debili (1, 5) , Isabelle Plo (1, 5) , Jason A Mills (13) , Deborah French (13) , Mitchell J Weiss (14) , Eric Solary (1, 5) , Rémi Favier (1, 15) , William Vainchenker (1, 5) , Hana Raslova (1, 5)

1 U1170 Inserm - Hématopoïèse normale et pathologique
2 Service d'Hématologie Biologique [Mondor]
3 UPD7 - Université Paris Diderot - Paris 7
4 Hôpital Henri Mondor
5 IGR - Institut Gustave Roussy
6 EPHE - École Pratique des Hautes Études
7 Service d’Oncologie Hématologique et Thérapie Cellulaire [CHU Poitiers]
8 PFEP - Plateforme d’évaluation préclinique
9 Service d'histologie, embryologie et cytogénétique [Béclère]
10 ONCOSTEM - Modèles de Cellules Souches Malignes et Thérapeutiques
11 Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy]
12 Faculté de Médecine [Nancy]
13 Department of Pathology and Laboratory Medicine [Children’s Hospital of Philadelphia]
14 Division of Hematology [Children's Hospital of Philadelphia]
15 CHU Trousseau [APHP]

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.

Domaines: Sciences du Vivant [q-bio]

Iléana Antony-Debré, Vladimir T Manchev, Nathalie Balayn, Dominique Bluteau, Cécile Tomowiak, et al.. Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia. Blood, 2015, 6 (125), pp.930-940. ⟨10.1182/blood-2014-06-585513⟩. ⟨hal-01681166⟩