ACSL5, a prognostic factor in acute myeloid leukemia, modulates the activity of Wnt/β-catenin signaling by palmitoylation modification

Abstract

Acyl-CoA synthetase long chain family member 5 (ACSL5), is a member of the acyl-CoA synthetases (ACSs) family that activates long chain fatty acids by catalyzing the synthesis of fatty acyl-CoAs. The dysregulation of ACSL5 has been reported in some cancers, such as glioma and colon cancers. However, little is known about the role of ACSL5 in acute myeloid leukemia (AML). We found that the expression of ACSL5 was higher in bone marrow cells from AML patients compared with that from healthy donors. ACSL5 level could serve as an independent prognostic predictor of the overall survival of AML patients. In AML cells, the ACSL5 knockdown inhibited cell growth both in vitro and in vivo. Mechanistically, the knockdown of ACSL5 suppressed the activation of the Wnt/β-catenin pathway by suppressing the palmitoylation modification of Wnt3a. Additionally, triacsin c, a pan-ACS family inhibitor, inhibited cell growth and robustly induced cell apoptosis when combined with ABT-199, the FDA approved BCL-2 inhibitor for AML therapy. Our results indicate that ACSL5 is a potential prognosis marker for AML and a promising pharmacological target for the treatment of molecularly stratified AML.

Keywords

acute myeloid leukemia / acyl-CoA synthetase long chain family member 5 / Wnt3a / palmitoylation / ABT-199

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Acknowledgements

We thank Prof. Guido Marcucci of the City of Hope Medical Center and Beckman Research Institute, Duarte, California, USA, for providing us the THP-1-luciferase cell line. This work was supported by the key international cooperation projects of the National Natural Science Foundation of China (No. 81820108004), the major projects of the Zhejiang Provincial Department of Science and Technology (No. 2021C03123), and the Pediatric Leukemia Diagnosis and Therapeutic Technology Research Center of Zhejiang Province (No. JBZX-201904).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-022-0942-1 and is accessible for authorized users.

Compliance with ethics guidelines

Wenle Ye, Jinghan Wang, Jiansong Huang, Xiao He, Zhixin Ma, Xia Li, Xin Huang, Fenglin Li, Shujuan Huang, Jiajia Pan, Jingrui Jin, Qing Ling, Yungui Wang, Yongping Yu, Jie Sun, and Jie Jin declare no conflict of interest. This study was approved by the ethics committee of the First Affiliated Hospital of Zhejiang University. All procedures followed were in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1975 as revised in 2000. Informed consents were obtained from all patients participating in this study. All institutional and national guidelines for the care and use of laboratory animals were also followed.

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