miRNA-1 promotes acute myeloid leukemia cell pathogenesis through metabolic regulation.

Autor:	Ghazaryan A; Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States., Wallace JA; Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States., Tang WW; Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States., Barba C; Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States., Lee SH; Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States., Bauer KM; Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States., Nelson MC; Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States., Kim CN; Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States., Stubben C; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States., Voth WP; Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States., Rao DS; Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, United States., O'Connell RM; Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States.; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in genetics [Front Genet] 2023 May 09; Vol. 14, pp. 1192799. Date of Electronic Publication: 2023 May 09 (Print Publication: 2023).
DOI:	10.3389/fgene.2023.1192799
Abstrakt:	Acute myeloid leukemia (AML) is a heterogeneous and deadly disease characterized by uncontrolled expansion of malignant blasts. Altered metabolism and dysregulated microRNA (miRNA) expression profiles are both 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 human AML cell lines, which decreased Oxidative Phosphorylation (OXPHOS). This metabolic shift also led to increased expression of miR-1 in the human AML cell lines tested. AML patient sample datasets 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 OXPHOS in miR-1 overexpressing MV4-11 cells, highlighting that miR-1 promotes OXPHOS through glutaminolysis. Finally, overexpression of miR-1 in AML cells exacerbated disease in a mouse xenograft model. Together, our work expands current knowledge within the field by uncovering novel connections between AML cell metabolism and miRNA expression that facilitates disease progression. Further, our work points to miR-1 as a potential new therapeutic target that may be used to disrupt AML cell metabolism and thus pathogenesis in the clinic. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Ghazaryan, Wallace, Tang, Barba, Lee, Bauer, Nelson, Kim, Stubben, Voth, Rao and O’Connell.)
Databáze:	MEDLINE
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