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Targeting STAT5 signaling overcomes resistance to IDH inhibitors in acute myeloid leukemia through suppression of stemness

ABSTRACT: Targeting STAT5 signaling overcomes resistance to IDH inhibitors in acute myeloid leukemia through suppression of stemness

PROVIDER: PRJNA899031 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22215302_1.fastq.gz	Fastqsanger.gz
	SRR22215302_2.fastq.gz	Fastqsanger.gz
	SRR22215303_1.fastq.gz	Fastqsanger.gz
	SRR22215303_2.fastq.gz	Fastqsanger.gz
	SRR22215304_1.fastq.gz	Fastqsanger.gz

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Targeting STAT5 signaling overcomes resistance to IDH inhibitors in acute myeloid leukemia through suppression of stemness

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Project description:Recurrent IDH mutations catalyze NADPH-dependent production of oncometabolite R-2HG for tumorigenesis. IDH inhibition provides clinical response in a subset of acute myeloid leukemia (AML) cases; however, most patients develop resistance, highlighting the need for more effective IDH-targeting therapies. By comparing transcriptomic alterations in isogenic leukemia cells harboring base-edited IDH mutations, we identify the activation of adhesion molecules including CD44, a transmembrane glycoprotein, as a shared feature of IDH-mutant leukemia. R-2HG-mediated CD44 upregulation is found in IDH-mutant AML patients of different cohorts. CD44 is indispensable for IDH-mutant leukemia cells through activating pentose phosphate pathway and inhibiting glycolysis by phosphorylating G6PD and PKM2, respectively. This metabolic rewiring ensures efficient NADPH generation for mutant IDH-catalyzed R-2HG production. Combining IDH inhibition with CD44 blockade enhances killing of IDH-mutant leukemia cells and overcomes resistance to IDH inhibition. Hence, we uncover an oncogenic feedforward pathway involving CD44-mediated metabolic rewiring for oncometabolite production, representing a targetable dependency of IDH-mutant malignancies.

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