{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T00:28:27Z","timestamp":1768696107105,"version":"3.49.0"},"reference-count":25,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T00:00:00Z","timestamp":1670371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["2202021"],"award-info":[{"award-number":["2202021"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Hematological Oncology"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Primary myelofibrosis (PMF) is characterized by immature megakaryocytic hyperplasia, splenomegaly, extramedullary hematopoiesis and bone marrow fibrosis. Our preclinical study had demonstrated that aurora kinase A (AURKA) inhibitor MLN8237 reduced the mutation burden of PMF by inducing differentiation of immature megakaryocytes. However, it only slightly alleviated splenomegaly, reduced tissue fibrosis, and normalized megakaryocytes in PMF patients of the preliminary clinical study. So enhancing therapeutic efficacy of PMF is needed. In this study, we found that AURKA directly interacted with heat shock protein 90\u00a0(HSP90) and HSP90 inhibitors promoted the ubiquitin\u2010dependent AURKA\u00a0degradation. We demonstrated that HSP90 inhibitors 17\u2010allylamino\u201017\u2010demethoxygeldanamycin (17\u2010AAG) and 17\u2010dimethylaminoethylamino\u201017\u2010demethoxygeldanamycin (17\u2010DMAG), normalized peripheral blood counts, improved splenomegaly, attenuated extramedullary hematopoiesis, decreased tissue fibrosis and reduced mutant burden in a MPLW515L mouse model of PMF. Importantly, both 17\u2010AAG and 17\u2010DMAG treatment at effective doses in vivo did not influence on hematopoiesis in healthy mice. Collectively, the study demonstrates that HSP90 inhibitors induce cell differentiation via the ubiquitin\u2010dependent AURKA and also are safe and effective for the treatment of a MPLW515L mouse model of PMF, which may provide a new strategy for PMF therapy. Further, we demonstrate that combined therapy shows superior activity in acute megakaryocytic leukemia mouse model than single therapy.<\/jats:p>","DOI":"10.1002\/hon.3110","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T19:48:45Z","timestamp":1669319325000},"page":"474-486","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Heat shock protein 90 inhibitors induce cell differentiation via the ubiquitin\u2010dependent aurora kinase A degradation in a MPLW515L mouse model of primary myelofibrosis"],"prefix":"10.1002","volume":"41","author":[{"given":"Fuping","family":"Wang","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Gene Resource and Molecular Development College of Life Sciences Beijing Normal University  Beijing 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