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.
X. Kang and J. Huang, "CAMKs Support Development of Acute Myeloid Leukemia," Journal of Hematology and Oncology, vol. 11, no. 1, BioMed Central, Feb 2018.
The definitive version is available at https://doi.org/10.1186/s13045-018-0574-8
Electrical and Computer Engineering
Intelligent Systems Center
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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01 Feb 2018