CAMKs support development of acute myeloid leukemia

Journal of Hematology & Oncology

Chen Wang¹  Jie Huang²  Meng Zhao³  Huimin Geng⁴  Huan-You Wang⁵  Markus Müschen⁶  Zhengshan Chen⁶  Changhao Cui⁷  Heyu Chen⁷  Zhigang Lu⁷  Cheng Cheng Zhang⁷  Xiaoli Chen⁷  Xunlei Kang⁷  Guojin Wu⁷  Li Wang⁸ 

[1]Center for Precision Medicine, Department of Medicine, University of Missouri

[2]Department of Electrical and Computer Engineering, Missouri University of Science and Technology

[3]Department of Hematology, The First Affiliated Hospital of Guangzhou Medical University

[4]Department of Laboratory Medicine, University of California San Francisco

[5]Department of Pathology, University of California San Diego

[6]Department of Systems Biology, Beckman Research Institute

[7]Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center

[8]School of Life Science and Medicine, Dalian University of Technology

关键词: Acute myeloid leukemia;    CAMK;    PirB;    LILRB2;    CREB;    Leukemic stem cell;   

DOI  :  10.1186/s13045-018-0574-8

来源: DOAJ

【 摘 要 】

Abstract Background We recently identified the human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse ortholog-paired Ig-like receptor (PirB) as receptors for several angiopoietin-like proteins (Angptls). We also demonstrated that PirB is important for the development of acute myeloid leukemia (AML), but exactly how an inhibitory receptor such as PirB can support cancer development is intriguing. Results Here, we showed that the activation of Ca (2+)/calmodulin-dependent protein kinases (CAMKs) is coupled with PirB signaling in AML cells. High expression of CAMKs is associated with a poor overall survival probability in patients with AML. Knockdown of CAMKI or CAMKIV decreased human acute leukemia development in vitro and in vivo. Mouse AML cells that are defective in PirB signaling had decreased activation of CAMKs, and the forced expression of CAMK partially rescued the PirB-defective phenotype in the MLL-AF9 AML mouse model. The inhibition of CAMK kinase activity or deletion of CAMKIV significantly slowed AML development and decreased the AML stem cell activity. We also found that CAMKIV acts through the phosphorylation of one of its well-known target (CREB) in AML cells. Conclusion CAMKs are essential for the growth of human and mouse AML. The inhibition of CAMK signaling may become an effective strategy for treating leukemia.

【 授权许可】

Unknown