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 & 3 others Matthew G. Vander Heiden, Craig B. Thompson, Ross L. Levine

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)789-804
Number of pages16
JournalJournal of Clinical Investigation
Volume128
Issue number2
DOIs
StatePublished - Feb 1 2018

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Isocitrate Dehydrogenase
Stem Cells
Neoplasms
Mutation
Acute Myeloid Leukemia
Epigenomics
Therapeutics
Bone Marrow
Gene Expression
Enzymes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

McKenney, A. S., Lau, A. N., Hanasoge Somasundara, A. V., Spitzer, B., Intlekofer, A. M., Ahn, J., ... Levine, R. L. (2018). JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition. Journal of Clinical Investigation, 128(2), 789-804. https://doi.org/10.1172/JCI94516

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

In: Journal of Clinical Investigation, Vol. 128, No. 2, 01.02.2018, p. 789-804.

Research output: Contribution to journalArticle

McKenney, AS, Lau, AN, Hanasoge Somasundara, AV, Spitzer, B, Intlekofer, AM, Ahn, J, Shank, K, Rapaport, FT, Patel, MA, Papalexi, E, Shih, AH, Chiu, A, Freinkman, E, Akbay, EA, Steadman, M, Nagaraja, R, Yen, K, Teruya-Feldstein, J, Wong, KK, Rampal, R, Vander Heiden, MG, Thompson, CB & Levine, RL 2018, 'JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition', Journal of Clinical Investigation, vol. 128, no. 2, pp. 789-804. https://doi.org/10.1172/JCI94516
McKenney AS, Lau AN, Hanasoge Somasundara AV, Spitzer B, Intlekofer AM, Ahn J et al. JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition. Journal of Clinical Investigation. 2018 Feb 1;128(2):789-804. https://doi.org/10.1172/JCI94516
McKenney, Anna Sophia ; Lau, Allison N. ; Hanasoge Somasundara, Amritha Varshini ; Spitzer, Barbara ; Intlekofer, Andrew M. ; Ahn, Jihae ; Shank, Kaitlyn ; Rapaport, Franck T. ; Patel, Minal A. ; Papalexi, Efthymia ; Shih, Alan H. ; Chiu, April ; Freinkman, Elizaveta ; Akbay, Esra A. ; Steadman, Mya ; Nagaraja, Raj ; Yen, Katharine ; Teruya-Feldstein, Julie ; Wong, Kwok Kin ; Rampal, Raajit ; Vander Heiden, Matthew G. ; Thompson, Craig B. ; Levine, Ross L. / JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 2. pp. 789-804.
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AU - McKenney, Anna Sophia

AU - Lau, Allison N.

AU - Hanasoge Somasundara, Amritha Varshini

AU - Spitzer, Barbara

AU - Intlekofer, Andrew M.

AU - Ahn, Jihae

AU - Shank, Kaitlyn

AU - Rapaport, Franck T.

AU - Patel, Minal A.

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AU - Freinkman, Elizaveta

AU - Akbay, Esra A.

AU - Steadman, Mya

AU - Nagaraja, Raj

AU - Yen, Katharine

AU - Teruya-Feldstein, Julie

AU - Wong, Kwok Kin

AU - Rampal, Raajit

AU - Vander Heiden, Matthew G.

AU - Thompson, Craig B.

AU - Levine, Ross L.

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N2 - 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.

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