Toxicology letters · 2026
Benzene metabolite-targeted gene ATF7IP2 drives glutamate metabolic reprogramming to promote acute myeloid leukemia initiation.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Zheng Shucong
Аннотация
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.
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.