Benzene metabolite-targeted gene ATF7IP2 drives glutamate metabolic reprogramming to promote acute myeloid leukemia initiation.

BACKGROUND

Benzene exposure is a recognized environmental risk factor for acute myeloid leukemia (AML). This study aimed to identify key drivers of benzene-associated AML and elucidate its pathogenic mechanisms.

METHODS

Candidate genes were screened by integrating two-sample Mendelian randomization (MR), transcriptomics, and single-cell sequencing data. Their biological functions were validated using functional experiments and metabolomics, and the efficacy of targeted interventions was assessed using in vivo and in vitro models.

RESULTS

Integrated analysis identified 138 genes associated with AML, among which ATF7IP2 was a reliable prognostic biomarker and independent risk factor. Benzene significantly upregulated ATF7IP2 expression in a dose-dependent manner. Mechanistically, ATF7IP2 is a key regulator of glutamate metabolism; knockdown of ATF7IP2 reduces intracellular glutamate/glutamine levels, thereby impairing cell viability and inducing cell cycle arrest, while exogenous glutamate can prevent these effects. scRNA-seq and trajectory analysis showed that in a benzene-associated microenvironment, ATF7IP2 drives the malignant differentiation of hematopoietic stem cells (HSCs) into a leukemia precursor stem cell (pre-LSC) subset. The peptidomimetic inhibitor TCMCB07, targeting this axis, inhibited leukemia cell proliferation, delayed disease progression, and prolonged mouse survival.

CONCLUSION

Our results indicate that ATF7IP2 is a key transcriptional metabolic hub that mediates benzene-induced AML by reprogramming glutamate metabolism and driving the conversion of HSCs to pre-LSCs.