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Chronic Myeloproliferative Neoplasias

AKT is a therapeutic target in myeloproliferative neoplasms

Leukemia volume 27, pages 1882–1890 (2013)Cite this article

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Abstract

The majority of patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN) harbor mutations in JAK2 or MPL, which lead to constitutive activation of the JAK/STAT, PI3K and ERK signaling pathways. JAK inhibitors by themselves are inadequate in producing selective clonal suppression in MPN and are associated with hematopoietic toxicities. MK-2206 is a potent allosteric AKT inhibitor that was well tolerated, including no evidence of myelosuppression, in a phase I study of solid tumors. Herein, we show that inhibition of PI3K/AKT signaling by MK-2206 affected the growth of both JAK2V617F- or MPLW515L-expressing cells via reduced phosphorylation of AKT and inhibition of its downstream signaling molecules. Moreover, we demonstrate that MK-2206 synergizes with ruxolitinib in suppressing the growth of JAK2V617F-mutant SET2 cells. Importantly, MK-2206 suppressed colony formation from hematopoietic progenitor cells in patients with primary myelofibrosis and alleviated hepatosplenomegaly and reduced megakaryocyte burden in the bone marrows, livers and spleens of mice with MPLW515L-induced MPN. Together, these findings establish AKT as a rational therapeutic target in the MPNs.

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Acknowledgements

We thank Jonathan Licht and Lou Dore for their helpful advice and critical reading of the manuscript. We also thank Merck for supplying MK-2206. This work was supported in part by grants from the NIH (CA101774 to JDC) and the Leukemia and Lymphoma Society, the Samuel Waxman Cancer Research Foundation, National Natural Science Foundation of China (Grant No. 30700412 and 81070406 to Z Huang). IK was supported by a T32 Grant to Northwestern University. IK is a recipient of the American Society of Hematology Translational Research Training in Hematology (TRTH) Award.

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  1. I Khan and Z Huang: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA

    I Khan, Q Wen, M J Stankiewicz, L Gilles, B Goldenson, R Schultz, L Diebold, B Stein, J K Altman & J D Crispino

  2. College of Life Science, Wuhan University, Wuhan, Hubei, PRC

    Z Huang

  3. Department of Pathology, University of Chicago, Chicago, IL, USA

    S Gurbuxani

  4. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    C M Finke, T L Lasho, A Pardanani & A Tefferi

  5. Department of Medicine, Human Oncology Program and Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering, New York, NY, USA

    P Koppikar & R L Levine

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  1. I Khan
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Correspondence to A Tefferi or J D Crispino.

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Author Contributions

IK, ZH, QW, LG, BG performed the experiments, analyzed the data and wrote the manuscript. PK, LD, MJS and RS assisted with experiments and animal studies. SG analyzed the data and assisted with the manuscript. CF, TL, QW, MS, AP, BS, JA and AT assisted with patient specimen experiments. RL, AT and JC analyzed the data and wrote the manuscript.

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Khan, I., Huang, Z., Wen, Q. et al. AKT is a therapeutic target in myeloproliferative neoplasms. Leukemia 27, 1882–1890 (2013). https://doi.org/10.1038/leu.2013.167

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