Abstract B1-18: Integrative analysis of gene expression and metabolism in isocitrate dehydrogenase 1 mutant acute myeloid leukemia and myeloid knock in mouse model

Abstract Isocitrate dehydrogenase 1 (IDH1) mutations are common drivers of acute myeloid leukemia (AML). While mutant IDH1 is known to disrupt DNA methylation, gene expression, and metabolism in cell lines, it is not known how mutant IDH1 alters global metabolism in vivo. The purpose of this study is to find differential enzymes and metabolites in IDH1 wild type versus mutant AML and knock in mice by integrating differential genes and metabolites in a metabolic network. Differential genes were found by comparing gene expression and DNA methylation in IDH1 mutant (n = 12) and wild type (n = 89) cytogenetically normal AML patients from The Cancer Genome Atlas. Differential metabolites were found by untargeted liquid chromatography-mass spectrometry of urine, plasma, and bone marrow hematopoietic stem and progenitor cells from unpaired 1-2 year old mixed-sex IDH1 myeloid knock in (n = 13) and control mice (n = 14). Integrative analysis was performed using the MetScape 2 Cytoscape plugin. 71 differential genes and 52 differential metabolites were mapped to the global metabolic network. The set of differential genes and metabolites formed 10 connected subnetworks containing reactions in sphingolipid, phospholipid, and bile acid metabolism. Two enzymes in the subnetworks were differentially expressed in an independent IDH1 mutant versus wild type AML dataset: acyl-CoA thioesterase 4 (ACOT4) and galactosylceramidase (GALC) (P < 0.05, false discovery rate ≤ 0.3). ACOT4 and GALC were significantly upregulated (P < 0.02) in acute promyelocytic leukemia cells treated with all-trans retinoic acid. In conclusion, we have found novel differential genes and metabolites in IDH1 mutant systems which may be relevant to leukemia differentiation treatment. Integrative analysis of gene expression and metabolite levels could be useful for finding dysregulated metabolic subnetworks in cancer. Citation Format: Alan Tseng, Wanda Li, Kim-Chung Lee, Karrie Yung, Ching-Wan Lam, Tak Mak. Integrative analysis of gene expression and metabolism in isocitrate dehydrogenase 1 mutant acute myeloid leukemia and myeloid knock in mouse model. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-18.