Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition

Qiang Jeremy Wen, Qiong Yang, Benjamin Goldenson, Sébastien Malinge, Terra Lasho, Rebekka K. Schneider, Lawrence J. Breyfogle, Rachael Schultz, Laure Gilles, Priya Koppikar, Omar Abdel-Wahab, Animesh D Pardanani, Brady Stein, Sandeep Gurbuxani, Ann Mullally, Ross L. Levine, Ayalew Tefferi, John D. Crispino

Research output: Contribution to journalArticle

55 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1473-1480
Number of pages8
JournalNature Medicine
Volume21
Issue number12
DOIs
StatePublished - Dec 1 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Jeremy Wen, Q., Yang, Q., Goldenson, B., Malinge, S., Lasho, T., Schneider, R. K., Breyfogle, L. J., Schultz, R., Gilles, L., Koppikar, P., Abdel-Wahab, O., Pardanani, A. D., Stein, B., Gurbuxani, S., Mullally, A., Levine, R. L., Tefferi, A., & Crispino, J. D. (2015). Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition. Nature Medicine, 21(12), 1473-1480. https://doi.org/10.1038/nm.3995