4.4 Article

Endothelial lipase promotes acute myeloid leukemia progression through metabolic reprogramming

Journal

NEOPLASMA
Volume 69, Issue 4, Pages 755-+

Publisher

AEPRESS SRO
DOI: 10.4149/neo_2022_211004N1408

Keywords

endothelial lipase; acute myeloid leukemia; lipid metabolism; DNA methyltransferase 3A

Categories

Funding

  1. National Natural Science Foundation of China [81770182]
  2. Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant [20152507]

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Metabolic reprogramming occurs in the clonal evolution of acute myeloid leukemia (AML) and affects multiple metabolic pathways, including lipid metabolism. Endothelial lipase (LIPG) may serve as a potential metabolic target for the treatment of AML with abnormal lipid metabolism.
Metabolic reprogramming occurs in the clonal evolution of acute myeloid leukemia (AML), which contributes to cell survival under metabolic stress and the development of drug resistance. Leukemic cells exhibit various metabolic profiles, which involve multiple metabolic pathways due to the heterogeneity of AML. However, studies on metabolic targets for AML treatment are mostly focused on glycolysis at present. In this work, we established conditional knock-in AML mouse models harboring Dnmt3aR878H/WT, NrasG12D/WT, and both of the mutations, respectively. Transcriptomic analysis of Gr1+ cells from bone marrow was performed afterward to screen interested metabolic pathways and target genes. Candidate genes were studied using the CRISPR/Cas9 technique, quantitative real-time RT-PCR, and flow cytometric analyses. We revealed that multiple metabolic pathways were affected in AML mice, including lipid metabolism. Endothelial lipase (LIPG) was obviously upregulated in leukemic cells from AML mice with Dnmt3a mutation. We performed knockout of LIPG in OCI-AML3 cells carrying DNMT3A R882C mutation by using the CRISPR/Cas9 technique. Depletion of LIPG led to proliferation inhibition, apoptosis, damage of antioxidant capacity, and myeloid differentiation in OCI-AML3 cells. LIPG might serve as a potential metabolic target for the treatment of AML with abnormal lipid metabolism.

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