Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis Journal Article

Authors: Koppikar, P.; Abdel-Wahab, O.; Hedvat, C.; Marubayashi, S.; Patel, J.; Goel, A.; Kucine, N.; Gardner, J. R.; Combs, A. P.; Vaddi, K.; Haley, P. J.; Burn, T. C.; Rupar, M.; Bromberg, J. F.; Heaney, M. L.; de Stanchina, E.; Fridman, J. S.; Levine, R. L.
Article Title: Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis
Abstract: The discovery of JAK2 and MPL mutations in patients with myeloproliferative neoplasms (MPNs) provided important insight into the genetic basis of these disorders and led to the development of JAK2 kinase inhibitors for MPN therapy. Although recent studies have shown that JAK2 kinase inhibitors demonstrate efficacy in a JAK2V617F murine bone marrow transplantation model, the effects of JAK2 inhibitors on MPLW515L-mediated myeloproliferation have not been investigated. In this report, we describe the in vitro and in vivo effects of INCB16562, a small-molecule JAK2 inhibitor. INCB16562 inhibited proliferation and signaling in cell lines transformed by JAK2 and MPL mutations. Compared with vehicle treatment, INCB16562 treatment improved survival, normalized white blood cell counts and platelet counts, and markedly reduced extramedullary hematopoeisis and bone marrow fibrosis. We observed inhibition of STAT3 and STAT5 phosphorylation in vivo consistent with potent inhibition of JAK-STAT signaling. These data suggest JAK2 inhibitor therapy may be of value in the treatment of JAK2V617F-negative MPNs. However, we did not observe a decrease in the size of the malignant clone in the bone marrow of treated mice at the end of therapy, which suggests that JAK2 inhibitor therapy, by itself, was not curative in this MPN model. © 2010 by The American Society of Hematology.
Keywords: signal transduction; protein phosphorylation; myelofibrosis; unclassified drug; gene mutation; mutation, missense; janus kinase 2; primary myelofibrosis; drug efficacy; nonhuman; cell proliferation; animal cell; mouse; animals; mice; stat3 protein; animal experiment; animal model; drug effect; drug screening assays, antitumor; enzyme inhibitor; cell line, tumor; phosphorylation; mice, inbred balb c; protein kinase inhibitors; hematologic neoplasms; hematopoietic cell; thrombocyte count; stat3 transcription factor; blood cell count; leukocyte count; disease models, animal; stat5 protein; stat5 transcription factor; thrombocytosis; platelet count; incb 16562; mpl gene; receptors, thrombopoietin
Journal Title: Blood
Volume: 115
Issue: 14
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2010-04-08
Start Page: 2919
End Page: 2927
Language: English
DOI: 10.1182/blood-2009-04-218842
PUBMED: 20154217
PROVIDER: scopus
PMCID: PMC2854434
Notes: --- - "Cited By (since 1996): 2" - "Export Date: 20 April 2011" - "CODEN: BLOOA" - "Source: Scopus"
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MSK Authors
  1. Mark L Heaney
    90 Heaney
  2. Jacqueline Bromberg
    105 Bromberg
  3. Cyrus Hedvat
    123 Hedvat
  4. Jyoti Patel
    7 Patel
  5. Nicole Kucine
    4 Kucine
  6. Ross Levine
    490 Levine
  7. Aviva J Goel
    7 Goel
  8. Jeffrey Gardner
    33 Gardner