Endothelial lipase promotes acute myeloid leukemia progression through metabolic reprogramming.

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.

Gene mutational pattern and expression level in 560 acute myeloid leukemia patients and their clinical relevance.

BACKGROUND: Cytogenetic aberrations and gene mutations have long been regarded as independent prognostic markers in AML, both of which can lead to misexpression of some key genes related to hematopoiesis. It is believed that the expression level of the key genes is associated with the treatment outcome of AML. METHODS: In this study, we analyzed the clinical features and molecular aberrations of 560 newly diagnosed non-M3 AML patients, including mutational status of CEBPA, NPM1, FLT3, C-KIT, NRAS, WT1, DNMT3A, MLL-PTD and IDH1/2, as well as expression levels of MECOM, ERG, GATA2, WT1, BAALC, MEIS1 and SPI1. RESULTS: Certain gene expression levels were associated with the cytogenetic aberration of the disease, especially for MECOM, MEIS1 and BAALC. FLT3, C-KIT and NRAS mutations contained conversed expression profile regarding MEIS1, WT1, GATA2 and BAALC expression, respectively. FLT3, DNMT3A, NPM1 and biallelic CEBPA represented the mutations associated with the prognosis of AML in our group. Higher MECOM and MEIS1 gene expression levels showed a significant impact on complete remission (CR) rate, disease free survival (DFS) and overall survival (OS) both in univariate and multivariate analysis, respectively; and an additive effect could be observed. By systematically integrating gene mutational status results and gene expression profile, we could establish a more refined system to precisely subdivide AML patients into distinct prognostic groups. CONCLUSIONS: Gene expression abnormalities contained important biological and clinical informations, and could be integrated into current AML stratification system.