Synapse - Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms

Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms Journal Article

Authors:	Rampal, R.; Ahn, J.; Abdel-Wahab, 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.; Verstovsek, S.; Rapaport, F.; Stephens, P. J.; Miller, V. A.; Levine, R. L.
Article Title:	Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms
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.
Keywords:	leukemia; genetics; mus; targeted therapy; myeloproliferative neoplasm; cancer biology
Journal Title:	Proceedings of the National Academy of Sciences of the United States of America
Volume:	111
Issue:	50
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Date Published:	2014-12-16
Start Page:	E5401
End Page:	E5410
Language:	English
DOI:	10.1073/pnas.1407792111
PROVIDER:	scopus
PMCID:	PMC4273376
PUBMED:	25516983
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84918570809&partnerID=40&md5=cc4546b9099e552cc3767ef209c62d39
Notes:	Export Date: 2 January 2015 -- Source: Scopus