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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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.).
The authors declare no competing financial interests.
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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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