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
Notes: Article -- Export Date: 1 March 2018 -- Source: Scopus
Citation Impact
MSK Authors
  1. Julie T Feldstein
    290 Feldstein
  2. Alan H Shih
    56 Shih
  3. Raajit Kumar Rampal
    158 Rampal
  4. Ross Levine
    541 Levine
  5. Barbara Spitzer
    35 Spitzer
  6. Minal A Patel
    45 Patel
  7. April Chiu
    56 Chiu
  8. Craig Bernie Thompson
    128 Thompson
  9. Kaitlyn Ruth Shank
    20 Shank
  10. Jihae Ahn
    11 Ahn