Targeting CaMKII-δ/DHCR24 axis is a novel strategy against acute myeloid leukemia

Author:

Wu Zhaoxing1,Gong Qinyuan1,Li Mengyuan1,Zheng Shuwen1,Zhang Xuzhao1,Wang Ping1,Liang Yun1,Xu Rongzhen1

Affiliation:

1. Zhejiang University

Abstract

Abstract Relapse is one of the biggest challenges in treating acute myeloid leukemia (AML) due to leukemia stem/progenitor cells resisting chemotherapy, providing a cellular reservoir to form the basis for relapse. Here, we identify CaMKII-δ/DHCR24 axis as a novel therapeutic target of AML. CaMKII-δ is aberrantly activated in leukemia stem/progenitor cells of AML patients but not in normal hematopoietic stem/progenitor cells, and associated with high tumor burden and poor outcome. Blocking CaMKII-δ activity results in rapid apoptosis of AML stem/progenitor and bulk leukemia cells by inhibiting STAT3, CDK6 and BCL-2 that regulate viability, cell cycle and apoptosis of AML cells. Moreover, CaMKII-δ is a key regulator of DHCR24 associated with cholesterol metabolic pathway of AML. Inhibition of DHCR24 selectively suppressed the growth of leukemia stem/progenitor cells. Importantly, we demonstrated that pharmacological inhibition of CaMKII-δ/DHCR24 axis by small molecule hesperadin potently regressed AML in mouse model. These findings reveal that CaMKII-δ3/DHCR24 axis is a critical regulator that differentially regulates the survival and apoptosis of AML cells and normal HSCs. CaMKII-δ/DHCR24 axis might be a potential therapeutic target for treating AML.

Publisher

Research Square Platform LLC

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