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Inhibition of pyrimidine biosynthesis targets protein translation in AML

ABSTRACT: Inhibition of pyrimidine biosynthesis targets protein translation in AML

PROVIDER: PRJNA752897 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15370107.fastq.gz	Fastqsanger.gz
	SRR15370109.fastq.gz	Fastqsanger.gz
	SRR15370111.fastq.gz	Fastqsanger.gz
	SRR15370113.fastq.gz	Fastqsanger.gz
	SRR15370115.fastq.gz	Fastqsanger.gz

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Inhibition of pyrimidine biosynthesis targets protein translation in AML.

Project description:The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anti-cancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) and has potent and selective activity against multiple AML subtypes. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.

| S-SCDT-EMM-2021-15203 | biostudies-other

Inhibition of pyrimidine biosynthesis targets protein translation in AML [RNA-seq_RUNX1]

Project description:Investigation of the transcriptional profile of AML in response to DHODH inhibition by AG636. RUNX1-RUNX1T1 cells were transplanted into Ptprca recipients. Mice bearing tumors were treated with AG636 for one day. Leukemic stem cells (cKit high; CD11b low) from bone marrow and spleen were isolated and RNA sequencing performed.

2022-04-26 | GSE181664 | GEO

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