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.


Electrical and Computer Engineering

Research Center/Lab(s)

Intelligent Systems Center


This work was supported by NIH (1R01CA172268), the Leukemia & Lymphoma Society (1024-14 and TRP-6024-14), March of Dimes Foundation (1-FY14-201), the Cancer Prevention and Research Institute of Texas (RP140402, DP150056), Robert A. Welch Foundation Award (I-1834), and Fundamental Research Funds for the Central Universities of China (No. 5006-851008).

Keywords and Phrases

Calcium calmodulin dependent protein kinase; Calcium calmodulin dependent protein kinase I; Calcium calmodulin dependent protein kinase IV; Cyclic AMP responsive element binding protein; Leukocyte immunoglobulin like receptor B2; Membrane protein; Mixed lineage leukemia protein; Unclassified drug; Acute myeloid leukemia; Acute myeloid leukemia cell line; Adult; Animal cell; Animal experiment; Animal model; Article; Cancer growth; Cancer inhibition; Controlled study; Disease association; Embryo; Enzyme activation; Enzyme activity; Enzyme inhibition; Enzyme phosphorylation; Gene deletion; Gene knockdown; Human; Human cell; Human tissue; In vitro study; In vivo study; Mouse; Nonhuman; Overall survival; Phenotype; Protein expression; Protein targeting; Signal transduction; Stem cell; Survival rate; Tumor xenograft; CAMK; CREB; Leukemic stem cell; LILRB2; PirB

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Article - Journal

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© 2018 The Author(s), All rights reserved.

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Publication Date

01 Feb 2018