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Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia

ABSTRACT: Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia

PROVIDER: PRJNA541936 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9029981.fastq.gz	Fastqsanger.gz
	SRR9029982.fastq.gz	Fastqsanger.gz
	SRR9029983.fastq.gz	Fastqsanger.gz
	SRR9029984.fastq.gz	Fastqsanger.gz
	SRR9029985.fastq.gz	Fastqsanger.gz

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Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia

Project description:To identify novel therapeutic targets in Acute Myeloid Leukemia (AML), we chemically interrogated 200 sequenced primary specimens. We identified Mubritinib, a known ERBB2 inhibitor, as a strong in vitro and in vivo anti-leukemic compound. We demonstrate that, in the context of AML, Mubritinib functions through ubiquinone-dependent inhibition of Electron Transport Chain (ETC) complex I activity. Resistance to Mubritinib characterized normal CD34+ hematopoietic cells and chemotherapy-sensitive AMLs, which displayed transcriptomic hallmarks of hypoxia. Conversely, sensitivity correlated with mitochondrial function-related gene expression levels and characterized a large subset of chemotherapy-resistant AMLs with oxidative phosphorylation (OXPHOS) hyperactivity. Altogether, our work thus identifies a novel ETC complex I inhibitor and reveals for the first time the genetic landscape of OXPHOS dependency in this disease.

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