Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms

Raajit Rampal, Jihae Ahn, Omar Abdel-Wahaba, Michelle Nahas, Kai Wang, Doron Lipson, Geoff A. Otto, Roman Yelensky, Todd Hricik, Anna Sophia McKenney, Gabriela Chiosis, Young Rock Chung, Suveg Pandey, Marcel R M Van Den Brink, Scott A. Armstrong, Ahmet Dogan, Andrew Intlekofer, Taghi Manshouri, Christopher Y. Park, Srdan VerstovsekFranck Rapaport, Philip J. Stephens, Vincent A. Miller, Ross L. Levine

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E5401-E5410
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number50
DOIs
StatePublished - Dec 16 2014
Externally publishedYes

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Keywords

  • Cancer biology
  • Genetics
  • Leukemia
  • Myeloproliferative neoplasm
  • Targeted therapy

ASJC Scopus subject areas

  • General

Cite this

Rampal, R., Ahn, J., Abdel-Wahaba, O., Nahas, M., Wang, K., Lipson, D., Otto, G. A., Yelensky, R., Hricik, T., McKenney, A. S., Chiosis, G., Chung, Y. R., Pandey, S., Van Den Brink, M. R. M., Armstrong, S. A., Dogan, A., Intlekofer, A., Manshouri, T., Park, C. Y., ... Levine, R. L. (2014). Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proceedings of the National Academy of Sciences of the United States of America, 111(50), E5401-E5410. https://doi.org/10.1073/pnas.1407792111