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 Pardanani; Brady Stein; Sandeep Gurbuxani; Ann Mullally; Ross L. Levine; Ayalew Tefferi; John D. Crispino

doi:10.1038/nm.3995

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 Pardanani, Brady Stein, Sandeep Gurbuxani, Ann Mullally, Ross L. Levine, Ayalew Tefferi, John D. Crispino^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

129 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 language	English (US)
Pages (from-to)	1473-1480
Number of pages	8
Journal	Nature Medicine
Volume	21
Issue number	12
DOIs	https://doi.org/10.1038/nm.3995
State	Published - Dec 1 2015

Funding

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.).

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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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., 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

@article{0134a401286046d38b954a1ab4d44b9d,

title = "Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition",

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.",

author = "{Jeremy Wen}, Qiang and Qiong Yang and Benjamin Goldenson and S{\'e}bastien Malinge and Terra Lasho and Schneider, {Rebekka K.} and Breyfogle, {Lawrence J.} and Rachael Schultz and Laure Gilles and Priya Koppikar and Omar Abdel-Wahab and Animesh Pardanani and Brady Stein and Sandeep Gurbuxani and Ann Mullally and Levine, {Ross L.} and Ayalew Tefferi and Crispino, {John D.}",

note = "Funding Information: 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{\textquoteright}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.).",

year = "2015",

month = dec,

day = "1",

doi = "10.1038/nm.3995",

language = "English (US)",

volume = "21",

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journal = "Nature Medicine",

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Jeremy Wen, Q, Yang, Q, Goldenson, B, Malinge, S, Lasho, T, Schneider, RK, Breyfogle, LJ, Schultz, R, Gilles, L, Koppikar, P, Abdel-Wahab, O, Pardanani, A, Stein, B, Gurbuxani, S, Mullally, A, Levine, RL, Tefferi, A & Crispino, JD 2015, 'Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition', Nature Medicine, vol. 21, no. 12, pp. 1473-1480. https://doi.org/10.1038/nm.3995

TY - JOUR

T1 - Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition

AU - Jeremy Wen, Qiang

AU - Yang, Qiong

AU - Goldenson, Benjamin

AU - Malinge, Sébastien

AU - Lasho, Terra

AU - Schneider, Rebekka K.

AU - Breyfogle, Lawrence J.

AU - Schultz, Rachael

AU - Gilles, Laure

AU - Koppikar, Priya

AU - Abdel-Wahab, Omar

AU - Pardanani, Animesh

AU - Stein, Brady

AU - Gurbuxani, Sandeep

AU - Mullally, Ann

AU - Levine, Ross L.

AU - Tefferi, Ayalew

AU - Crispino, John D.

N1 - Funding Information: 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.).

PY - 2015/12/1

Y1 - 2015/12/1

N2 - 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.

AB - 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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Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition

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