Title | Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Rampal R, Ahn J, Abdel-Wahab O, Nahas M, Wang K, Lipson D, Otto GA, Yelensky R, Hricik T, McKenney ASophia, Chiosis G, Chung YRock, Pandey S, van den Brink MRM, Armstrong SA, Dogan A, Intlekofer A, Manshouri T, Park CY, Verstovsek S, Rapaport F, Stephens PJ, Miller VA, Levine RL |
Journal | Proc Natl Acad Sci U S A |
Volume | 111 |
Issue | 50 |
Pagination | E5401-10 |
Date Published | 2014 Dec 16 |
ISSN | 1091-6490 |
Keywords | Animals, Azacitidine, Benzodioxoles, Blotting, Western, Colony-Forming Units Assay, Exome, Flow Cytometry, Hematologic Neoplasms, High-Throughput Nucleotide Sequencing, Humans, Janus Kinase 2, Leukemia, Myeloid, Acute, Mice, Mutation, Missense, Myeloproliferative Disorders, Purines, Pyrazoles, Tumor Suppressor Protein p53 |
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. |
DOI | 10.1073/pnas.1407792111 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 25516983 |
PubMed Central ID | PMC4273376 |
Grant List | P30 CA016672 / CA / NCI NIH HHS / United States UL1 RR024996 / RR / NCRR NIH HHS / United States 5F30CA183497 / CA / NCI NIH HHS / United States R01 CA155226 / CA / NCI NIH HHS / United States T32GM007739 / GM / NIGMS NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States K08 CA188529 / CA / NCI NIH HHS / United States R01 CA172546 / CA / NCI NIH HHS / United States R01 CA151949 / CA / NCI NIH HHS / United States 1R01CA151949-01 / CA / NCI NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States UL1 TR000457 / TR / NCATS NIH HHS / United States F30 CA183497 / CA / NCI NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:09pm