JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition Journal Article
| Authors: | McKenney, A. S.; Lau, A. N.; Hanasoge Somasundara, A. V.; Spitzer, B.; Intlekofer, A. M.; Ahn, J.; Shank, K.; Rapaport, F. T.; Patel, M. A.; Papalexi, E.; Shih, A. H.; Chiu, A.; Freinkman, E.; Akbay, E. A.; Steadman, M.; Nagaraja, R.; Yen, K.; Teruya-Feldstein, J.; Wong, K. K.; Rampal, R.; Vander Heiden, M. G.; Thompson, C. B.; Levine, R. L. |
| Article Title: | 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. |
| Keywords: | adult; controlled study; aged; middle aged; gene mutation; human cell; janus kinase 2; cancer growth; drug efficacy; monotherapy; nonhuman; drug targeting; animal cell; mouse; animal tissue; cell compartmentalization; cell function; cd34 antigen; enzyme inhibition; gene expression; animal experiment; animal model; in vivo study; cell differentiation; carcinogenesis; stem cell; drug mechanism; erythrocyte; cell expansion; myeloproliferative neoplasm; 2 hydroxyglutaric acid; isocitrate dehydrogenase 1; isocitrate dehydrogenase 2; ruxolitinib; disease burden; human; male; female; priority journal; article; enasidenib; inc 18424 |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 128 |
| Issue: | 2 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2018-02-01 |
| Start Page: | 789 |
| End Page: | 804 |
| Language: | English |
| DOI: | 10.1172/jci94516 |
| PROVIDER: | scopus |
| PMCID: | PMC5785272 |
| PUBMED: | 29355841 |
| DOI/URL: | |
| Notes: | Erratum issued, see DOI: [10.1172/JCI124920] -- Source: Scopus |
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