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Chronic Myeloproliferative Neoplasias

EXEL-8232, a small-molecule JAK2 inhibitor, effectively treats thrombocytosis and extramedullary hematopoiesis in a murine model of myeloproliferative neoplasm induced by MPLW515L

Leukemia volume 26, pages 720–727 (2012)Cite this article

Abstract

About 10% of patients with essential thrombocythemia (ET) or myelofibrosis (MF) that lack mutations in JAK2 harbor an activating mutation in the thrombopoietin receptor, MPLW515L. Distinct from the JAK2V617F retroviral transplant model, the MPLW515L model recapitulates many features of ET and MF, including severe fibrosis and thrombocytosis. We have tested EXEL-8232, an experimental potent JAK2 inhibitor, for efficacy in suppression of thrombocytosis in vivo and for its ability to attenuate MPLW515L myeloproliferative disease. EXEL-8232 was administered for 28 days q12 h by oral gavage at doses of 30 or 100 mg/kg, prospectively. Animals treated with EXEL-8232 at 100 mg/kg had normalized high platelet counts, eliminated extramedullary hematopoiesis in the spleen and eliminated bone marrow fibrosis, whereas the wild-type controls did not develop thrombocytopenia. Consistent with a clinical response in this model, we validated surrogate end points for response to treatment, including a reduction of endogenous colony growth and signaling inhibition in immature erythroid and myeloid primary cells both in vitro and upon treatment in vivo. We conclude that EXEL-8232 has efficacy in treatment of thrombocytosis in vivo in a murine model of ET and MF, and may be of therapeutic benefit for patients with MPL-mutant MPN.

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Acknowledgements

GW designed and performed the research, analyzed the data and wrote the paper. MGK, AM, DSL and RO performed research. TG analyzed data and reviewed pathology. DOC contributed vital new reagents. DGG supervised the research and wrote the paper. We are grateful to Maricel Gozo, Mahnaz Paktinat, Erika Haydu, Brian Ball, Tulasi Khandan for technical support.

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Authors and Affiliations

  1. Department of Pathology, Stanford University School of Medicine, Stanford Hospital and Clinics, Stanford, CA, USA

    G Wernig & T George

  2. Department of Hematology, Harvard Medical School, Brigham & Women's Hosp., Boston, MA, USA

    G Wernig, M G Kharas, A Mullally, D S Leeman & R Okabe

  3. Translational Medicine, Exelixis, South San Francisco, CA, USA

    D O Clary

  4. Merck & Co. Inc., North Wales, PA, USA

    D G Gilliland

Authors
  1. G Wernig
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  2. M G Kharas
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  3. A Mullally
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  4. D S Leeman
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  5. R Okabe
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  6. T George
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  7. D O Clary
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  8. D G Gilliland
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Corresponding author

Correspondence to G Wernig.

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Competing interests

The Leukemia and Lymphoma Society provided salary support for GW. DOC is employed at Exelixis. The remaining authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Leukemia website

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Wernig, G., Kharas, M., Mullally, A. et al. EXEL-8232, a small-molecule JAK2 inhibitor, effectively treats thrombocytosis and extramedullary hematopoiesis in a murine model of myeloproliferative neoplasm induced by MPLW515L. Leukemia 26, 720–727 (2012). https://doi.org/10.1038/leu.2011.261

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