Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition

Nature Medicine

Volumn 21, Issue 12, 2015, Pages 1473-1480

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

^a NORTHWESTERN UNIVERSITY   (United States)

^b INSTITUT GUSTAVE ROUSSY   (France)

^c MAYO CLINIC   (United States)

^d BRIGHAM AND WOMEN S HOSPITAL   (United States)

^e MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^f UNIVERSITY OF CHICAGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALISERTIB; RUXOLITINIB; STAT5 PROTEIN; AURORA A KINASE; AZEPINE DERIVATIVE; CD34 ANTIGEN; JAK2 PROTEIN, HUMAN; JANUS KINASE 2; MPL PROTEIN, HUMAN; MYC PROTEIN; PROTEIN KINASE INHIBITOR; PYRAZOLE DERIVATIVE; PYRIMIDINE DERIVATIVE; THROMBOPOIETIN RECEPTOR;

ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; BODY WEIGHT; CANCER COMBINATION CHEMOTHERAPY; CELL DIFFERENTIATION; CLINICAL FEATURE; COLONY FORMATION; CONTROLLED STUDY; DRUG POTENTIATION; DRUG TARGETING; GROWTH INHIBITION; IC50; IN VIVO STUDY; MEGAKARYOCYTE; MOUSE; MYELOID METAPLASIA; MYELOID PROGENITOR CELL; MYELOPROLIFERATIVE NEOPLASM; NONHUMAN; PATHOGENESIS; POLYPLOIDY; PRIORITY JOURNAL; SINGLE DRUG DOSE; SOMATIC MUTATION; ANIMAL; ANTAGONISTS AND INHIBITORS; APOPTOSIS; CELL PROLIFERATION; COST OF ILLNESS; DISEASE MODEL; DRUG EFFECTS; ENZYMOLOGY; GENETICS; HETEROZYGOTE; METABOLISM; MUTATION; PATHOLOGY; SIGNAL TRANSDUCTION; TUMOR CELL LINE; WESTERN BLOTTING;

ANIMALS; ANTIGENS, CD34; APOPTOSIS; AURORA KINASE A; AZEPINES; BLOTTING, WESTERN; CELL DIFFERENTIATION; CELL LINE, TUMOR; CELL PROLIFERATION; COST OF ILLNESS; DISEASE MODELS, ANIMAL; DRUG SYNERGISM; HETEROZYGOTE; INHIBITORY CONCENTRATION 50; JANUS KINASE 2; MEGAKARYOCYTES; MICE; MUTATION; POLYPLOIDY; PRIMARY MYELOFIBROSIS; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-MYC; PYRAZOLES; PYRIMIDINES; RECEPTORS, THROMBOPOIETIN; SIGNAL TRANSDUCTION;

EID: 84949623272     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.3995     Document Type: Article

References (44)

1. Gangat, N. et al. DIPSS plus: A refined dynamic international prognostic scoring system for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count and transfusion status. J. Clin. Oncol. 29, 392-397 (2011).
2. Mascarenhas, J. & Hoffman, R. A comprehensive review and analysis of the effect of ruxolitinib therapy on the survival of patients with myelofibrosis. Blood 121, 4832-4837 (2013).
3. Ciurea, S.O. et al. Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis. Blood 110, 986-993 (2007).
4. Vannucchi, A.M. et al. Mutations and prognosis in primary myelofibrosis. Leukemia 27, 1861-1869 (2013).
5. Abdel-Wahab, O. et al. Unraveling the genetic underpinnings of myeloproliferative neoplasms and understanding their effect on disease course and response to therapy: Proceedings from the 6th international Post-ASH Symposium. Am. J. Hematol. 87, 562-568 (2012).
6. Tibes, R., Bogenberger, J.M., Benson, K.L. & Mesa, R.A. Current outlook on molecular pathogenesis and treatment of myeloproliferative neoplasms. Mol. Diagn. Ther. 16, 269-283 (2012).
7. Klampfl, T. et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N. Engl. J. Med. 369, 2379-2390 (2013).
8. Nangalia, J. et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N. Engl. J. Med. 369, 2391-2405 (2013).
9. Verstovsek, S. et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N. Engl. J. Med. 366, 799-807 (2012).
10. Harrison, C. et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N. Engl. J. Med. 366, 787-798 (2012).
11. Tefferi, A. JAK inhibitors for myeloproliferative neoplasms: Clarifying facts from myths. Blood 119, 2721-2730 (2012).
12. Tam, C.S. & Verstovsek, S. Investigational Janus kinase inhibitors. Expert Opin. Investig. Drugs 22, 687-699 (2013).
13. Harrison, C. et al. Practical management of patients with myelofibrosis receiving ruxolitinib. Expert Rev. Hematol. 6, 511-523 (2013).
14. Villeval, J.L. et al. High thrombopoietin production by hematopoietic cells induces a fatal myeloproliferative syndrome in mice. Blood 90, 4369-4383 (1997).
15. Shivdasani, R.A., Fujiwara, Y., McDevitt, M.A. & Orkin, S.H. A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J. 16, 3965-3973 (1997).
16. Vannucchi, A.M. et al. Development of myelofibrosis in mice genetically impaired for GATA-1 expression (GATA-1low mice). Blood 100, 1123-1132 (2002).
17. Wen, Q. et al. Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL. Cell 150, 575-589 (2012).
18. Goldenson, B. & Crispino, J.D. The Aurora kinases in cell cycle and leukemia. Oncogene 34, 537-545 (2015).
19. Levine, R.L. et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia and myeloid metaplasia with myelofibrosis. Cancer Cell 7, 387-397 (2005).
20. Stachura, D.L., Chou, S.T. & Weiss, M.J. Early block to erythromegakaryocytic development conferred by loss of transcription factor GATA-1. Blood 107, 87-97 (2006).
21. Vannucchi, A.M. et al. Abnormalities of GATA-1 in megakaryocytes from patients with idiopathic myelofibrosis. Am. J. Pathol. 167, 849-858 (2005).
22. Uozumi, K. et al. Establishment and characterization of a new human megakaryoblastic cell line (SET-2) that spontaneously matures to megakaryocytes and produces platelet-like particles. Leukemia 14, 142-152 (2000).
23. Mullally, A. et al. Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. Cancer Cell 17, 584-596 (2010).
24. Goldenson, B., Kirsammer, G., Stankiewicz, M.J., Wen, Q.J. & Crispino, J.D. Aurora kinase A is required for hematopoiesis but is dispensable for mouse megakaryocyte endomitosis and differentiation. Blood 125, 2141-2150 (2015).
25. den Hollander, J. et al. Aurora kinases A and B are upregulated by Myc and are essential for maintenance of the malignant state. Blood 116, 1498-1505 (2010).
26. Wernig, G. et al. The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes. Blood 111, 3751-3759 (2008).
27. Sumi, K., Tago, K., Kasahara, T. & Funakoshi-Tago, M. Aurora kinase A critically contributes to the resistance to anticancer drug cisplatin in JAK2V617F mutant-induced transformed cells. FEBS Lett. 585, 1884-1890 (2011).
28. Koppikar, P. et al. Efficacy of the JAK2 inhibitor INCB16562 in a mouse model of MPLW515L-induced thrombocytosis and myelofibrosis. Blood 115, 2919-2927 (2010).
29. Wernig, G. et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a mouse model of JAK2V617F-induced polycythemia vera. Cancer Cell 13, 311-320 (2008).
30. Cowley, D.O. et al. Aurora A kinase is essential for bipolar spindle formation and early development. Mol. Cell. Biol. 29, 1059-1071 (2009).
31. Castro-Malaspina, H. Pathogenesis of myelofibrosis: Role of ineffective megakaryopoiesis and megakaryocyte components. Prog. Clin. Biol. Res. 154, 427-454 (1984).
32. Le Bousse-Kerdilès, M.C. & Martyre, M. C. & French INSERM Research Network on Idiopathic Myeolofibrosis. Involvement of the fibrogenic cytokines, TGF-? and bFGF, in the pathogenesis of idiopathic myelofibrosis. Pathol. Biol. (Paris) 49, 153-157 (2001).
33. Martyré, M.C., Magdelenat, H., Bryckaert, M.C., Laine-Bidron, C. & Calvo, F. Increased intraplatelet levels of platelet-derived growth factor and transforming growth factor-? in patients with myelofibrosis with myeloid metaplasia. Br. J. Haematol. 77, 80-86 (1991).
34. Bock, O. et al. Bone morphogenetic proteins are overexpressed in the bone marrow of primary myelofibrosis and are apparently induced by fibrogenic cytokines. Am. J. Pathol. 172, 951-960 (2008).
35. Hoermann, G. et al. Identification of oncostatin M as a JAK2V617F-dependent amplifier of cytokine production and bone marrow remodeling in myeloproliferative neoplasms. FASEB J. 26, 894-906 (2012).
36. Chagraoui, H. et al. Prominent role of TGF-?1 in thrombopoietin-induced myelofibrosis in mice. Blood 100, 3495-3503 (2002).
37. Bruns, I. et al. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat. Med. 20, 1315-1320 (2014).
38. Zhao, M.P.J. et al. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat. Med. 20, 1321-1326 (2014).
39. Schepers, K. et al. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. Cell Stem Cell 13, 285-299 (2013).
40. Dodson, C.A., Yeoh, S., Haq, T. & Bayliss, R. A kinetic test characterizes kinase intramolecular and intermolecular autophosphorylation mechanisms. Sci. Signal. 6, ra54 (2013).
41. Chou, T.C. & Talalay, P. Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 22, 27-55 (1984).
42. Kühn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427-1429 (1995).
43. de Boer, J. et al. Transgenic mice with hematopoietic and lymphoid specific expression of Cre. Eur. J. Immunol. 33, 314-325 (2003).
44. Akashi, K., Traver, D., Miyamoto, T. & Weissman, I.L. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193-197 (2000).