Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies | Zendy

Joseph Saliba | Zendy; Cécile SaintMartin | Zendy; Antonio Di Stefano | Zendy; Gaëlle Lenglet | Zendy; Caroline Marty | Zendy; Boris Keren | Zendy; Florence Pasquier | Zendy; Véronique Della Valle | Zendy; Lise Secardin | Zendy; Gwendoline Leroy | Zendy; Emna Mahfoudhi | Zendy; Sarah Grosjean | Zendy; Nathalie Droin | Zendy; M’Boyba Diop | Zendy; Philippe Dessen | Zendy; Sabine Charrier | Zendy; Alberta Palazzo | Zendy; Jane Merlevede | Zendy; Jean-Côme Meniane | Zendy; Christine Delaunay-Darivon | Zendy; Pascal Fuseau | Zendy; Françoise Isnard | Zendy; Nicole Casadevall | Zendy; Éric Solary | Zendy; Najet Debili | Zendy; Olivier Bernard | Zendy; Hana Raslová | Zendy; A Najman | Zendy; William Vainchenker | Zendy; Christine BellannéChantelot | Zendy; Isabelle Plo | Zendy

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Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies

Author(s) -

Joseph Saliba,

Cécile SaintMartin,

Antonio Di Stefano,

Gaëlle Lenglet,

Caroline Marty,

Boris Keren,

Florence Pasquier,

Véronique Della Valle,

Lise Secardin,

Gwendoline Leroy,

Emna Mahfoudhi,

Sarah Grosjean,

Nathalie Droin,

M’Boyba Diop,

Philippe Dessen,

Sabine Charrier,

Alberta Palazzo,

Jane Merlevede,

Jean-Côme Meniane,

Christine Delaunay-Darivon,

Pascal Fuseau,

Françoise Isnard,

Nicole Casadevall,

Éric Solary,

Najet Debili,

Olivier Bernard,

Hana Raslová,

A Najman,

William Vainchenker,

Christine BellannéChantelot,

Isabelle Plo

Publication year - 2015

Publication title -

nature genetics

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 18.861

H-Index - 573

eISSN - 1546-1718

pISSN - 1061-4036

DOI - 10.1038/ng.3380

Subject(s) - biology , gene duplication , germline , myeloid , haematopoiesis , progenitor cell , myeloproliferative neoplasm , cancer research , germline mutation , genetics , induced pluripotent stem cell , stem cell , mutation , immunology , gene , myelofibrosis , embryonic stem cell , bone marrow

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.

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