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High expression of BCAT1 sensitizes AML cells to PARP inhibitor by suppressing DNA damage response.
Pan, Jiajia; Wang, Yungui; Huang, Shujuan; Mao, Shihui; Ling, Qing; Li, Chenying; Li, Fenglin; Yu, Mengxia; Huang, Xin; Huang, Jiansong; Lv, Yunfei; Li, Xia; Ye, Wenle; Wang, Huafeng; Wang, Jinghan; Jin, Jie.
Afiliación
  • Pan J; Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, No.79 Qingchun Road, Hangzhou, 310003, Zhejiang, People's Republic of China.
  • Wang Y; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, China.
  • Huang S; Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, No.79 Qingchun Road, Hangzhou, 310003, Zhejiang, People's Republic of China.
  • Mao S; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, China.
  • Ling Q; Department of Hematology, the First Affiliated Hospital of University of Science and Technology of China, Anhui, Hefei, China.
  • Li C; Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, No.79 Qingchun Road, Hangzhou, 310003, Zhejiang, People's Republic of China.
  • Li F; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, China.
  • Yu M; Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, No.79 Qingchun Road, Hangzhou, 310003, Zhejiang, People's Republic of China.
  • Huang X; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, China.
  • Huang J; Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, No.79 Qingchun Road, Hangzhou, 310003, Zhejiang, People's Republic of China.
  • Lv Y; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, China.
  • Li X; Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, No.79 Qingchun Road, Hangzhou, 310003, Zhejiang, People's Republic of China.
  • Ye W; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, China.
  • Wang H; Department of Hematology, Affiliated Hangzhou First People's Hospital, Zhejiang University College of Medicine, Hangzhou, China.
  • Wang J; Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, No.79 Qingchun Road, Hangzhou, 310003, Zhejiang, People's Republic of China.
  • Jin J; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, China.
J Mol Med (Berl) ; 102(3): 415-433, 2024 03.
Article en En | MEDLINE | ID: mdl-38340163
ABSTRACT
Previous evidence has confirmed that branched-chain aminotransferase-1 (BCAT1), a key enzyme governing branched-chain amino acid (BCAA) metabolism, has a role in cancer aggression partly by restricting αKG levels and inhibiting the activities of the αKG-dependent enzyme family. The oncogenic role of BCAT1, however, was not fully elucidated in acute myeloid leukemia (AML). In this study, we investigated the clinical significance and biological insight of BCAT1 in AML. Using q-PCR, we analyzed BCAT1 mRNAs in bone marrow samples from 332 patients with newly diagnosed AML. High BCAT1 expression independently predicts poor prognosis in patients with AML. We also established BCAT1 knockout (KO)/over-expressing (OE) AML cell lines to explore the underlying mechanisms. We found that BCAT1 affects cell proliferation and modulates cell cycle, cell apoptosis, and DNA damage/repair process. Additionally, we demonstrated that BCAT1 regulates histone methylation by reducing intracellular αKG levels in AML cells. Moreover, high expression of BCAT1 enhances the sensitivity of AML cells to the Poly (ADP-ribose) polymerase (PARP) inhibitor both in vivo and in vitro. Our study has demonstrated that BCAT1 expression can serve as a reliable predictor for AML patients, and PARP inhibitor BMN673 can be used as an effective treatment strategy for patients with high BCAT1 expression. KEY MESSAGES High expression of BCAT1 is an independent risk factor for poor prognosis in patients with CN-AML. High BCAT1 expression in AML limits intracellular αKG levels, impairs αKG-dependent histone demethylase activity, and upregulates H3K9me3 levels. H3K9me3 inhibits ATM expression and blocks cellular DNA damage repair process. Increased sensitivity of BCAT1 high expression AML to PARP inhibitors may be used as an effective treatment strategy in AML patients.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Antineoplásicos Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: J Mol Med (Berl) Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2024 Tipo del documento: Article Pais de publicación: Alemania

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Antineoplásicos Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: J Mol Med (Berl) Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2024 Tipo del documento: Article Pais de publicación: Alemania