Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies

J. Saliba (1) , C. Saint-Martin (1) , A. Di Stefano (1) , G. Lenglet (1) , C. Marty (1) , B. Keren (2) , F. Pasquier (3, 1) , V. D. Valle (1) , L. Secardin (1) , G. Leroy (2) , E. Mahfoudhi (1) , S. Grosjean (1) , N. Droin (4) , M'Boyba Diop (1) , P. Dessen (1) , S. Charrier (5) , A. Palazzo (1) , J. Merlevede (1) , J. C. Meniane , C. Delaunay-Darivon , P. Fuseau , F. Isnard (6) , N. Casadevall (1) , E. Solary (1) , N. Debili (1) , O. A. Bernard (1) , H. Raslova (1) , A. Najman (6) , W. Vainchenker (1) , C. Bellanne-Chantelot (7, 1, 2) , I. Plo (1)

1 U1170 Inserm - Hématopoïèse normale et pathologique
2 CHU Pitié-Salpêtrière [AP-HP]
3 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
4 Hématopoïèse normale et pathologique
5 INTEGRARE - Approches génétiques intégrées et nouvelles thérapies pour les maladies rares
6 CHU Saint-Antoine [AP-HP]
7 UPMC - Université Pierre et Marie Curie - Paris 6

No major predisposition gene for familial myeloproliferative neoplasms (MPN) has been identified. Here we demonstrate that the autosomal dominant transmission of a 700-kb duplication in four genetically related families predisposes to myeloid malignancies, including MPN, frequently progressing to leukemia. Using induced pluripotent stem cells and primary cells, we demonstrate that overexpression of ATG2B and GSKIP enhances hematopoietic progenitor differentiation, including of megakaryocytes, by increasing progenitor sensitivity to thrombopoietin (TPO). ATG2B and GSKIP cooperate with acquired JAK2, MPL and CALR mutations during MPN development. Thus, the germline duplication may change the fitness of cells harboring signaling pathway mutations and increases the probability of disease development.

Domaines: Génomique, Transcriptomique et Protéomique [q-bio.GN]; Cancer; Hématologie

J. Saliba, C. Saint-Martin, A. Di Stefano, G. Lenglet, C. Marty, et al.. Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies. Nature Genetics, 2015, 47 (10), pp.1131-1140. ⟨10.1038/ng.3380⟩. ⟨hal-02881018⟩