Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms Academic Article uri icon


MeSH Major

  • Hematologic Neoplasms
  • Janus Kinase 2
  • Leukemia, Myeloid, Acute
  • Myeloproliferative Disorders
  • Tumor Suppressor Protein p53


  • Patients with myeloproliferative neoplasms (MPNs) are at significant, cumulative risk of leukemic transformation to acute myeloid leukemia (AML), which is associated with adverse clinical outcome and resistance to standard AML therapies. We performed genomic profiling of post-MPN AML samples; these studies demonstrate somatic tumor protein 53 (TP53) mutations are common in JAK2V617F-mutant, post-MPN AML but not in chronic-phase MPN and lead to clonal dominance of JAK2V617F/TP53-mutant leukemic cells. Consistent with these data, expression of JAK2V617F combined with Tp53 loss led to fully penetrant AML in vivo. JAK2V617F-mutant, Tp53-deficient AML was characterized by an expanded megakaryocyte erythroid progenitor population that was able to propagate the disease in secondary recipients. In vitro studies revealed that post-MPN AML cells were sensitive to decitabine, the JAK1/2 inhibitor ruxolitinib, or the heat shock protein 90 inhibitor 8-(6-iodobenzo[d][1.3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purine-6-amine (PU-H71). Treatment with ruxolitinib or PU-H71 improved survival of mice engrafted with JAK2V617F-mutant, Tp53-deficient AML, demonstrating therapeutic efficacy for these targeted therapies and providing a rationale for testing these therapies in post-MPN AML.

publication date

  • December 16, 2014



  • Academic Article



  • eng

PubMed Central ID

  • PMC4273376

Digital Object Identifier (DOI)

  • 10.1073/pnas.1407792111

PubMed ID

  • 25516983

Additional Document Info

start page

  • E5401

end page

  • 10


  • 111


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