A Novel Role for Malate Dehydrogenase 1 in Acute Myeloid Leukemia Progression

The tumor suppressor role of the metabolic genes is rarely reported. Here, we report that malate dehydrogenase 1 (MDH1) acts as an anti-oncogene in acute myeloid leukemia (AML) progression. In a screen of various leukemia cell lines, as well as peripheral blood mononuclear cells from patients with AML and healthy individuals, we observed that patients with AML had lower mRNA expression of MDH1 than healthy individuals. In addition, we found that overexpression of MDH1 in the AML cell lines MV4-11 and THP-1 in vitro promoted their differentiation, reduced their growth, induced apoptosis, and increased the proportion of cells in S phase, which were more sensitive to the chemotherapeutic drugs cytarabine and daunorubicin. Using an in vivo xenograft mouse model of AML, we found that disruption of MDH1 expression influenced tumor burden and mouse survival. These findings were consistent with an inverse relationship between MDH1 expression and overall survival in two independent cohorts of AML patients. We also identified changes in the expression of other genes, concomitant with reduced MDH1 expression in patients with AML, that largely explain the anti-oncogenic role of MDH1 in AML progression. Notably, downregulation of P53 and upregulation of the MAPK pathway in low MDH1-expressing MV4-11 cells were reversed upon overexpression of MDH1. In conclusion, we demonstrated that MDH1 plays a tumor-suppressing role in AML and can be used as a novel mimic drug therapy in the future.