Journal Article

Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms

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

2014

Overview

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 JAK2 V617F - mutant, post-MPN AML but not in chronic-phase MPN and lead to clonal dominance of JAK2 V617F /TP53- mutant leukemic cells. Consistent with these data, expression of JAK2 V617F combined with Tp53 loss led to fully penetrant AML in vivo. JAK2 V617F-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 JAK2 V617F-mutant, Tp53 -deficient AML, demonstrating therapeutic efficacy for these targeted therapies and providing a rationale for testing these therapies in post-MPN AML. Significance Myeloproliferative neoplasms (MPN) are chronic hematopoietic disorders characterized by clonal proliferation of mature myeloid elements. A subset of MPNs transforms to acute myeloid leukemia (AML). The mechanisms and pathways that contribute to transformation from MPN to AML have not been well delineated. We have characterized the somatic mutational spectrum of post-MPN AML and demonstrate that somatic tumor protein 53 ( TP53 ) mutations are common in JAK2 V617F - mutant, post-MPN AML but not in chronic-phase MPN. We demonstrate that expression of JAK2 V617F combined with Tp53 loss in a murine model leads to fully penetrant AML in vivo . We have characterized this model and used it to test therapeutic strategies. These data reveal novel insights into the pathogenesis of, and potential therapeutic strategies for, leukemic transformation.

• Publisher: National Academy of Sciences
• Subject: animal models / Animals / Azacitidine - analogs & derivatives / Azacitidine - pharmacology / Benzodioxoles - pharmacology / Biological Sciences / Blotting, Western / Cells / Clinical outcomes / Colony-Forming Units Assay / Exome - genetics / Flow Cytometry / Genetics / Hematologic Neoplasms - complications / High-Throughput Nucleotide Sequencing / Humans / Janus Kinase 2 - genetics / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - etiology / Leukemia, Myeloid, Acute - genetics / Mice / Mutants / Mutation / Mutation, Missense - genetics / myeloid leukemia / Myeloproliferative Disorders - complications / Myeloproliferative Disorders - genetics / non-specific protein-tyrosine kinase / pathogenesis / PNAS Plus / Proteins / Purines - pharmacology / Pyrazoles - pharmacology / Tumor Suppressor Protein p53 - genetics / Tumors