JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition
Anna Sophia McKenney, Allison N. Lau, Amritha Varshini Hanasoge Somasundara, Barbara Spitzer, Andrew M. Intlekofer, Jihae Ahn, Kaitlyn Shank, Franck T. Rapaport, Minal A. Patel, Efthymia Papalexi, Alan H. Shih, April Chiu, Elizaveta Freinkman, Esra A. Akbay, Mya Steadman, Raj Nagaraja, Katharine Yen, Julie Teruya-Feldstein, Kwok-Kin Wong, Raajit Rampal, Matthew G. Vander Heiden, Craig B. Thompson, Ross L. Levine
Anna Sophia McKenney, Allison N. Lau, Amritha Varshini Hanasoge Somasundara, Barbara Spitzer, Andrew M. Intlekofer, Jihae Ahn, Kaitlyn Shank, Franck T. Rapaport, Minal A. Patel, Efthymia Papalexi, Alan H. Shih, April Chiu, Elizaveta Freinkman, Esra A. Akbay, Mya Steadman, Raj Nagaraja, Katharine Yen, Julie Teruya-Feldstein, Kwok-Kin Wong, Raajit Rampal, Matthew G. Vander Heiden, Craig B. Thompson, Ross L. Levine
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Research Article Hematology Oncology

JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition

Abstract

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.

Authors

Anna Sophia McKenney, Allison N. Lau, Amritha Varshini Hanasoge Somasundara, Barbara Spitzer, Andrew M. Intlekofer, Jihae Ahn, Kaitlyn Shank, Franck T. Rapaport, Minal A. Patel, Efthymia Papalexi, Alan H. Shih, April Chiu, Elizaveta Freinkman, Esra A. Akbay, Mya Steadman, Raj Nagaraja, Katharine Yen, Julie Teruya-Feldstein, Kwok-Kin Wong, Raajit Rampal, Matthew G. Vander Heiden, Craig B. Thompson, Ross L. Levine

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Figure 2

Combined mutant mice have expanded pathological stem and progenitor cell populations.

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Combined mutant mice have expanded pathological stem and progenitor cell...
(A) Peripheral blood donor chimerism of competitive transplants with Idh2R140Q Jak2V617F bone marrow over time (n = 5/group) and at 12 weeks (n = 5–50/group). (B) Peripheral blood chimerism, hematocrit levels, and platelet counts in recipients of bone marrow sorted for MPP or LT-HSC LSK populations, 15 weeks after injection (n = 5/group). (C) Total number of LSK cells and (D) total number of myeloprogenitor cells in bone marrow from primary Idh2R140Q Jak2V617F mice and controls according to stem cell/progenitor compartment as measured by FACS (n = 4–5/group). (E) Stem cell populations as measured by FACS in peripheral blood and bone marrow from primary Idh2R140Q Jak2V617F mice, expressed as a percentage of lineage-negative cells. (F) MkP cell populations, (G) erythrocytic progenitor cell populations, and (H) granulocytic progenitor cell populations as measured by FACS in bone marrow from primary Idh2R140Q Jak2V617F mice, expressed as a proportion of lineage-negative cells (n = 4–5/group). Multiple comparisons were performed using an ordinary 1-way ANOVA with Tukey’s correction for post-hoc comparisons and multiplicity-corrected P values. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.