Format

Send to

Choose Destination
Nat Genet. 2015 Oct;47(10):1131-40. doi: 10.1038/ng.3380. Epub 2015 Aug 17.

Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.

Saliba J1,2,3,4, Saint-Martin C1,2,3,5, Di Stefano A1,2,3,4, Lenglet G1,2,3,4, Marty C1,2,3,4, Keren B5, Pasquier F1,2,3,4, Valle VD1,2,3, Secardin L1,2,3,4, Leroy G5, Mahfoudhi E1,2,3,4,6, Grosjean S1,2,3,4, Droin N1,2,3, Diop M1,2,3, Dessen P1,2,3, Charrier S7, Palazzo A1,2,3, Merlevede J1,2,3, Meniane JC8, Delaunay-Darivon C8, Fuseau P9, Isnard F10,11, Casadevall N1,12, Solary E1,2,3, Debili N1,2,3, Bernard OA1,2,3, Raslova H1,2,3, Najman A10,11, Vainchenker W1,2,3,4,13, Bellanné-Chantelot C1,2,3,5,11, Plo I1,2,3,4.

Author information

1
INSERM, Unité Mixte de Recherche (UMR) 1170, Villejuif, France.
2
Université Paris XI, UMR 1170, Gustave Roussy, Villejuif, France.
3
Gustave Roussy, Villejuif, France.
4
Laboratory of Excellence GR-Ex, Villejuif, France.
5
Assistance Publique-Hôpitaux de Paris, Département de Génétique, Hôpital Pitié-Salpêtrière, Paris, France.
6
Laboratoire d'Hématologie Moléculaire et Cellulaire (Salem Abbes), Institut Pasteur de Tunis, Belvédère, Tunisia.
7
Généthon, Evry, France.
8
Service de Médecine Interne, Centre Hospitalier Universitaire (CHU) de Fort de France, Fort de France, France.
9
Laboratoire d'Hématologie, CHU Fort de France, Fort de France, France.
10
Assistance Publique-Hôpitaux de Paris, Département d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint-Antoine, Paris, France.
11
Sorbonne Universités, Université Pierre et Marie Curie (UPMC), Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques (GRC 7, MYPAC), Paris, France.
12
Assistance Publique-Hôpitaux de Paris, Laboratoire d'Hématologie, Hôpital Saint-Antoine, Paris, France.
13
Assistance Publique-Hôpitaux de Paris, Consultation d'Immuno-Hématologie, Hôpital Saint-Louis, Paris, France.

Abstract

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.

PMID:
26280900
DOI:
10.1038/ng.3380
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center