CAMKs support development of acute myeloid leukemia

Xunlei Kang, Changhao Cui, Chen Wang, Guojin Wu, Heyu Chen, Zhigang Lu, Xiaoli Chen, Li Wang, Jie Huang, Huimin Geng, Meng Zhao, Zhengshan Chen, Markus Müschen, Huan You Wang, Chengcheng Zhang

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Article number30
JournalJournal of Hematology and Oncology
Volume11
Issue number1
DOIs
StatePublished - Feb 27 2018

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Calcium-Calmodulin-Dependent Protein Kinases
Acute Myeloid Leukemia
Myeloid Cells
Leukemia
Angiopoietins
Myeloid Progenitor Cells
Immunoglobulins
Leukocytes
Phosphotransferases
Phosphorylation
Phenotype
Survival

Keywords

  • Acute myeloid leukemia
  • CAMK
  • CREB
  • Leukemic stem cell
  • LILRB2
  • PirB

ASJC Scopus subject areas

  • Hematology
  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

CAMKs support development of acute myeloid leukemia. / Kang, Xunlei; Cui, Changhao; Wang, Chen; Wu, Guojin; Chen, Heyu; Lu, Zhigang; Chen, Xiaoli; Wang, Li; Huang, Jie; Geng, Huimin; Zhao, Meng; Chen, Zhengshan; Müschen, Markus; Wang, Huan You; Zhang, Chengcheng.

In: Journal of Hematology and Oncology, Vol. 11, No. 1, 30, 27.02.2018.

Research output: Contribution to journalArticle

Kang, X, Cui, C, Wang, C, Wu, G, Chen, H, Lu, Z, Chen, X, Wang, L, Huang, J, Geng, H, Zhao, M, Chen, Z, Müschen, M, Wang, HY & Zhang, C 2018, 'CAMKs support development of acute myeloid leukemia', Journal of Hematology and Oncology, vol. 11, no. 1, 30. https://doi.org/10.1186/s13045-018-0574-8
Kang, Xunlei ; Cui, Changhao ; Wang, Chen ; Wu, Guojin ; Chen, Heyu ; Lu, Zhigang ; Chen, Xiaoli ; Wang, Li ; Huang, Jie ; Geng, Huimin ; Zhao, Meng ; Chen, Zhengshan ; Müschen, Markus ; Wang, Huan You ; Zhang, Chengcheng. / CAMKs support development of acute myeloid leukemia. In: Journal of Hematology and Oncology. 2018 ; Vol. 11, No. 1.
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AU - Kang, Xunlei

AU - Cui, Changhao

AU - Wang, Chen

AU - Wu, Guojin

AU - Chen, Heyu

AU - Lu, Zhigang

AU - Chen, Xiaoli

AU - Wang, Li

AU - Huang, Jie

AU - Geng, Huimin

AU - Zhao, Meng

AU - Chen, Zhengshan

AU - Müschen, Markus

AU - Wang, Huan You

AU - Zhang, Chengcheng

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AB - 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.

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