Dataset Information

CAMKs support development of acute myeloid leukemia.

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.

SUBMITTER: Kang X

PROVIDER: S-EPMC5828341 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Publications

CAMKs support development of acute myeloid leukemia.

Kang Xunlei X Cui Changhao C Wang Chen C Wu Guojin G Chen Heyu H Lu Zhigang Z Chen Xiaoli X Wang Li L Huang Jie J Geng Huimin H Zhao Meng M Chen Zhengshan Z Müschen Markus M Wang Huan-You HY Zhang Cheng Cheng CC

Journal of hematology & oncology 20180227 1

<h4>Background</h4>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.<h4>Results</h4>Here, we showed that the activation of Ca (2+)/calmodulin-dependent pr ...[more]

PMID: 29482582

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Project description:Acute myeloid leukemia (AML) is a malignancy of transformed hematopoietic progenitors, which is curable in only 25-50% of patients thus the risk of relapse remains the major challenge. Considerable efforts in improving outcome through the understanding of AML biology elucidate that AML is not autonomous but rather supported by a complex multicellular-bone marrow microenvironment for leukemogenesis, leukemia expansion, and chemoresistance. Within the microenvironment, bone marrow mesenchymal stroma cells (BMSC) safeguard leukemia allowing rapid growth and enable resistance to therapy. Herein, we modeled leukemia-stroma interactions to unravel the reciprocal signaling processes regulating leukemic cell growth and survival. First, we conducted a proteomic analysis of primary AML samples (n=13) cocultured with non-malignant stroma cells by utilizing liquid chromatography mass spectrometry (LC-MS/MS) to understand how the stroma contributes to AML cellular signaling. In the analysis, 84 proteins were significantly affected including upregulation of rate-limiting metabolic enzymatic proteins NAMPT, FASN, and HK1 in AML-stroma cocultures relative to AML monoculture. Through an epigenetic drug screen, we modeled stroma mediated protection of leukemia and uncovered prominent drug resistance by histone deacytlase inhibitor (HDACi) treatment in cocultured leukemic cell lines and cocultured primary AML. We performed a quantitative phosphoproteomics analysis of AML-stroma interactions of leukemic KG1a cells in monoculture and in coculture with stroma (Hs5) treated with HDACi. We uncovered phosphorylation networks of stroma mediated protection enriched in pathways involved in AMP-activated signaling, glucose catabolic processes and EGF/EGFR signaling with the most potent changes in hyper-phosphorylation of acetyl-coenzyme A synthetase (ACSS2, S30) and of hypo-phosphorylation acetyl-coenzyme A carboxylase alpha, (ACACA, S80) both of which are involved in acetyl-CoA (acetyl-CoA) utilization for fatty acid synthesis pathway. Validating these findings, we found that ACSS2 substrate, acetate, contributed to leukemic proliferative growth and ACSS2 loss impacted leukemia metabolic fitness. In addition, we uncovered a novel subgroup of AML patients based on high expression of ACSS1 or ACSS2, which significantly correlated with inferior outcome. The differentially upregulated genes of this ACSS1/2-high subgroup revealed a metabolic gene signature related to mitochondrial processes suggesting the metabolic state of AML may aid in predicting outcome. Our findings elucidate phosphoproteome network of AML-stroma interactions whereby overriding stroma mediated protection, we conclude, requires intervening the metabolic support by ACSS2 in AML.

Dataset Information

CAMKs support development of acute myeloid leukemia.

Background

Results

Conclusion

Publications

CAMKs support development of acute myeloid leukemia.

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