Heat shock protein 90 inhibitors induce cell differentiation via the ubiquitin-dependent aurora kinase A degradation in a MPLW515L mouse model of primary myelofibrosis.

Abstract

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 (HSP90) and HSP90 inhibitors promoted the ubiquitin-dependent AURKA degradation. We demonstrated that HSP90 inhibitors 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), 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-AAG and 17-DMAG 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-dependent 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.

• Authors: Fuping Wang, Haotian Zhang, Binghong He, Zihan Liu, Xinxin Wu, Yuankai Liu, Xin Xu, Xiaoxue Gou, Haitao Wang, Qiong Yang
• Journal: Hematological oncology (Hematol Oncol) Vol. 41 Issue 3 Pg. 474-486 (Aug 2023) ISSN: 1099-1069 [Electronic] England
• PMID: 36422297 (Publication Type: Journal Article)
• Copyright: © 2022 John Wiley & Sons Ltd.

Chemical References

• tanespimycin
• 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
• Aurora Kinase A
• Ubiquitin
• Antineoplastic Agents
• Heat-Shock Proteins

Topics

• Mice
• Humans
• Animals
• Primary Myelofibrosis (drug therapy, genetics)
• Aurora Kinase A
• Splenomegaly (drug therapy)
• Ubiquitin (pharmacology, therapeutic use)
• Cell Differentiation (genetics)
• Antineoplastic Agents (therapeutic use)
• Fibrosis
• Heat-Shock Proteins (pharmacology, therapeutic use)