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 5

Expression in donor-derived (CD45.2+) LSK cells by RNA-seq defines the gene set of combined mutant disease, and treatment eradicates this expression profile.

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Expression in donor-derived (CD45.2+) LSK cells by RNA-seq defines the ...
(A–E) RNA-seq analysis of donor derived (CD45.2+) LSK cells in Idh2R140Q Jak2V617F bone marrow recipients treated with targeted inhibitors (n = 3/group). (A) Significantly enriched Hallmark GSEA in comparative expression patterns comparing vehicle/diseased mice to WT. (B) Clustering of all treated mice depicting comparative phylogeny of samples and relative expression of the 100 most significantly differentially expressed genes. (C) Examination of genes differentially expressed between combined treatment mice and vehicle-treated mice using a gene set defined according to genes differentially expressed between WT and vehicle-treated mice. (D and E) Calculated normalized enrichment score (NES) values (y axis) and FDR (x axis) of curated Hallmark GSEA showing the level and significance of enrichment in each treatment group compared with WT examined for enrichment in curated Hallmark GSEA lists related to JAK/STAT signaling. Statistically significantly non-zero NES values are depicted in bright colors, while nonstatistically significant NES values are depicted in pastel colors. (D) Hallmark GSEA highlighting several pathways related to JAK/STAT signaling and (E) several oncogenic pathways. (F) Quantitative PCR for Gata1 and Gata2 expression performed on sorted MEPs from drug-treated mice. See Methods for details on the statistical methods used for the bioinformatics analysis in A and C. 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.