Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Autophagy-Related Proteins
  • Child
  • Chromosomes, Human, Pair 14
  • Female
  • Gene Duplication*
  • Genetic Predisposition to Disease*
  • Germ Cells*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Infant
  • Leukemia, Myeloid, Acute / genetics*
  • Male
  • Myelodysplastic Syndromes / genetics*
  • Pedigree
  • Phenotype
  • Repressor Proteins / genetics*
  • Vesicular Transport Proteins / genetics*
  • Young Adult


  • ATG2B protein, human
  • Autophagy-Related Proteins
  • GSKIP protein, human
  • Repressor Proteins
  • Vesicular Transport Proteins