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Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition

Nature Medicine volume 21, pages 1473–1480 (2015)Cite this article

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Abstract

Primary myelofibrosis (PMF) is characterized by bone marrow fibrosis, myeloproliferation, extramedullary hematopoiesis, splenomegaly and leukemic progression. Moreover, the bone marrow and spleens of individuals with PMF contain large numbers of atypical megakaryocytes that are postulated to contribute to fibrosis through the release of cytokines, including transforming growth factor (TGF)-β. Although the Janus kinase inhibitor ruxolitinib provides symptomatic relief, it does not reduce the mutant allele burden or substantially reverse fibrosis. Here we show through pharmacologic and genetic studies that aurora kinase A (AURKA) represents a new therapeutic target in PMF. Treatment with MLN8237, a selective AURKA inhibitor, promoted polyploidization and differentiation of megakaryocytes with PMF-associated mutations and had potent antifibrotic and antitumor activity in vivo in mouse models of PMF. Moreover, heterozygous deletion of Aurka was sufficient to ameliorate fibrosis and other PMF features in vivo. Our data suggest that megakaryocytes drive fibrosis in PMF and that targeting them with AURKA inhibitors has the potential to provide therapeutic benefit.

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Figure 1: AURKA inhibition induces differentiation, polyploidization, apoptosis and the arrest of proliferation in primary mouse MPN cells.
Figure 2: AURKA inhibition selectively induces polyploidization and differentiation of CD34+ cells isolated from the peripheral blood of individuals with PMF.
Figure 3: Inhibition of AURKA significantly reduces disease burden in the MPLW515L mouse model of myelofibrosis.
Figure 4: MLN8237 treatment reduces the disease burden of Jak2V617F-induced MPN in vivo.
Figure 5: Heterozygous deletion of Aurka is sufficient to reduce disease burden in the MPLW515L mouse model of myelofibrosis.
Figure 6: MLN8237 and ruxolitinib act synergistically both in vitro and in vivo.

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Acknowledgements

We thank A. Stern, J. Licht, Z. Huang and members of the Crispino lab for helpful discussions, and T. Van Dyke (National Cancer Institute) for the generous gift of Aurka-floxed mice. We also thank Z. Huang (Wuhan University) for providing the CALR T1 and CALR T2 plasmids, G. Gilliland (Fred Hutchinson Cancer Research Center) for the MPLW515L construct, M. Weiss (St. Jude Children's Research Hospital) for the G1ME cells and T. Arima (Kagoshima University) for the SET-2 cells. This work was supported by US National Institutes of Health (NIH) grant no. HL112792 (J.D.C.), a Leukemia and Lymphoma Society Translational Research Project grant (J.D.C.), the Samuel Waxman Cancer Research Foundation (J.D.C.), a Dixon Young Investigator Award from Northwestern Memorial Foundation (Q.J.W.), the Northwestern University Clinical and Translational Sciences Institute (Q.J.W.) and American Cancer Society grant no. 278808 (Q.J.W.). The project was also supported by the National Center for Research Resources (NCRR), the National Center for Advancing Translational Sciences (NCATS) and the NIH through grant no. TL1R000108 (B.G.).

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  1. Qiang Jeremy Wen and Qiong Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, Illinois, USA

    Qiang Jeremy Wen, Qiong Yang, Benjamin Goldenson, Rachael Schultz, Laure Gilles, Brady Stein & John D Crispino

  2. Institut Gustave Roussy, Paris, France

    Sébastien Malinge

  3. Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA

    Terra Lasho, Animesh Pardanani & Ayalew Tefferi

  4. Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Rebekka K Schneider, Lawrence J Breyfogle & Ann Mullally

  5. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Priya Koppikar, Omar Abdel-Wahab & Ross L Levine

  6. Section of Hematopathology, University of Chicago, Chicago, Illinois, USA

    Sandeep Gurbuxani

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Contributions

Q.J.W., Q.Y., B.G., S.M., L.J.B., R.S., L.G. and P.K. performed experiments, interpreted data and contributed to the writing of the manuscript. T.L., A.P., B.S. and A.T. provided patient specimens, interpreted data and contributed to the writing of the manuscript. S.G. and R.K.S. analyzed pathology, interpreted data and contributed to the writing of the manuscript. O.A.-W., A.M., R.L.L. and J.D.C. designed experiments, interpreted data and wrote the manuscript.

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Correspondence to John D Crispino.

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Jeremy Wen, Q., Yang, Q., Goldenson, B. et al. Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition. Nat Med 21, 1473–1480 (2015). https://doi.org/10.1038/nm.3995

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