TY - JOUR
T1 - JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition
AU - McKenney, Anna Sophia
AU - Lau, Allison N.
AU - Hanasoge Somasundara, Amritha Varshini
AU - Spitzer, Barbara
AU - Intlekofer, Andrew M.
AU - Ahn, Jihae
AU - Shank, Kaitlyn
AU - Rapaport, Franck T.
AU - Patel, Minal A.
AU - Papalexi, Efthymia
AU - Shih, Alan H.
AU - Chiu, April
AU - Freinkman, Elizaveta
AU - Akbay, Esra A.
AU - Steadman, Mya
AU - Nagaraja, Raj
AU - Yen, Katharine
AU - Teruya-Feldstein, Julie
AU - Wong, Kwok Kin
AU - Rampal, Raajit
AU - Vander Heiden, Matthew G.
AU - Thompson, Craig B.
AU - Levine, Ross L.
N1 - Funding Information:
ASM was supported by a Ruth L. Kirschstein National Research Service Award from the National Cancer Institute (NCI), NIH (F30CA183497) and a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the NIH (T32GM007739) to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program. ANL is a Robert Black Fellow of the Damon Runyon Cancer Research Foundation (DRG-2241-15). AHS was supported by a grant from the NCI (K08CA181507). EF was supported by a grant from the Department of Defense Peer-Reviewed Medical Research Program (W81XWH-15-1-0337). MGVH was supported in part by a Faculty Scholar grant from the Howard Hughes Medical Institute and also acknowledges support from Step Up 2 Cancer, NIH NCI (P50CA165962, P30CA14051) and the Koch Institute – Dana-Farber Harvard Cancer Center Bridge Project. RLL was supported by the Leukemia and Lymphoma Society’s (LLS) Specialized Center of Research (SCOR) program and NIH grants (U54OD020355-01, NCI R01CA172636, and R35CA197594). Flow cytometric and genomic analysis in this study and use of core facilities were funded in part through an NIH, NCI Cancer Center Support Grant (P30 CA008747). The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617F and mutant IDH1R132H or Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617F Idh2R140Q–mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mut and IDH2mut mutations. Taken together, these data suggest that combined JAK and IDH inhibition May offer a therapeutic advantage in this high-risk MPN subtype.
AB - Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617F and mutant IDH1R132H or Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617F Idh2R140Q–mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mut and IDH2mut mutations. Taken together, these data suggest that combined JAK and IDH inhibition May offer a therapeutic advantage in this high-risk MPN subtype.
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U2 - 10.1172/JCI94516
DO - 10.1172/JCI94516
M3 - Article
C2 - 29355841
AN - SCOPUS:85041473110
SN - 0021-9738
VL - 128
SP - 789
EP - 804
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -