MiRNA-1 promotes Acute Myeloid Leukemia cell pathogenesis through metabolic regulation [miRNA]

ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous and deadly disease characterized by uncontrolled expansion of malignant blasts. The current treatment for AML patients includes intensive chemotherapy and high-risk hematopoietic stem cell transplantation, highlighting the need for less toxic and more effective therapies. Altered metabolism and dysregulated microRNA (miRNA) expression profiles are characteristic of AML. However, there is a paucity of studies exploring how changes in the metabolic state of the leukemic cells regulate miRNA expression leading to altered cellular behavior. Here, we blocked pyruvate entry into mitochondria by deleting the Mitochondria Pyruvate Carrier (MPC1) gene in MV4-11 and Molm-14 human AML cell lines, which decreased Oxidative Phosphorylation (OXPHOS). The loss of MPC1 led to increased expression of miR-1 in both human AML cell lines tested. AML patient sample analysis showed that higher miR-1 expression correlates with reduced survival. Transcriptional and metabolic profiling of miR-1 overexpressing AML cells revealed that miR-1 increased OXPHOS, along with key metabolites that fuel the TCA cycle such as glutamine and fumaric acid. Inhibition of glutaminolysis decreased the elevated OXPHOS in miR-1 overexpressing MV4-11 cells, highlighting that miR-1 regulates OXPHOS through glutaminolysis. Further, the overexpression of miR-1 in AML cells exacerbated disease in a mouse xenograft model. Our work expands current knowledge within the field by uncovering novel connections between AML cell metabolism and miRNA expression that facilitates disease progression. Together, our work points to miR-1 as a potential new therapeutic target that can be used to disrupt AML cell metabolism and thus pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220133 | GEO | 2023/08/11

REPOSITORIES: GEO