JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition
Anna Sophia McKenney, … , Craig B. Thompson, Ross L. Levine
Anna Sophia McKenney, … , Craig B. Thompson, Ross L. Levine
Published January 22, 2018
Citation Information: J Clin Invest. 2018;128(2):789-804. https://doi.org/10.1172/JCI94516.
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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 1

Combined Jak2/IDH-mutant mice have lethal MPN with preleukemic features.

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Combined Jak2/IDH-mutant mice have lethal MPN with preleukemic features....
(A) Hematocrit levels and leukocyte counts in peripheral blood, (B) spleen weights, (C) 2HG levels in plasma, and (D) representative histology images for CD34 immunohistochemical stains of bone marrow and H&E stains of splenic tissue from primary IDH1R132H Jak2V617F Mx1-Cre mice sacrificed at approximately 6 months of age (n = 5/group). (E) Hematocrit levels and leukocyte counts in peripheral blood, (F) spleen weights, (G) 2HG levels in plasma, and (H) representative histology images for CD34 immunohistochemical stains of bone marrow, Wright-Giemsa stains of bone marrow cytospins, and H&E stains of splenic tissue from primary Idh2R140Q Jak2V617F Mx1-Cre mice sacrificed at approximately 6 months of age (n = 4–5/group). (I) Kaplan-Meier survival curve for primary IDH1R132H Jak2V617F Mx1-Cre mice following recombination. (J) Kaplan-Meier survival curve for secondary-transplant mice following injection of IDH1R132H Jak2V617F Mx1-Cre bone marrow. Scale bars: 200 μm. Multiple comparisons were performed using an ordinary 1-way ANOVA with Tukey’s correction for post-hoc comparisons and multiplicity-corrected P values. Comparisons of survival were performed using the log-rank (Mantel-Cox) test. Statistical interaction calculated for influence of Jak2 mutation status and IDH1 mutation status combined using 2-way ANOVA. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 by 2-way ANOVA. JAKmt, JAK-mutant; IDHmt, IDH-mutant; JAKmt/IDHmt, JAK/IDH-mutant.