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High expression of BCAT1 sensitizes AML cells to PARP inhibitor by suppressing DNA damage response

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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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Availability of data and material

TCGA microarray data that were available from the TCGA Research Network (http://cancergenome.nih.gov) via download from the CBio Portal for Cancer Genomics (http://www.cbioportal. org/public-portal/index.do) under the AML data sets. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

BCAT1 :

Branched-chain aminotransferase 1

PARPi:

Poly (ADP-ribose) polymerase (PARP) inhibitor

CR:

Response rate

BCAAs:

Branched-chain amino acids

αKG :

Alpha-ketoglutarate

BCAAs:

Branched-chain amino acids

BCKAs:

Branched-chain keto acids

2HG:

2-Hydroxyglutarate

OS:

Overall survival

EFS:

Event free survival

FAHZU:

First Affiliated Hospital of Zhejiang University

KO:

Knockout

OE:

Overexpressing

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Acknowledgements

We would like to thank Professor Ravi Bhatia for providing the MV4-11and OCI-AML3 cell lines and Professor Rongzhen Xu for providing the MV4-11-luc cell line used in these experiments. We are very thankful to the members of the Key Laboratory of Hematologic Malignancies for their support for the experimental installation and scientific discussion.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81820108004 and No. 81900154), Natural Science Foundation of Zhejiang Province, China (LQ18H080001), and National Natural Science Foundation of China Young Scientists Fund (No. 82300170).

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Author notes

  1. Jiajia Pan, Yungui Wang and Shujuan Huang contributed equally.

Authors and Affiliations

  1. Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, No.79 Qingchun Road, Hangzhou, 310003, Zhejiang, People’s Republic of China

    Jiajia Pan, Yungui Wang, Shihui Mao, Qing Ling, Chenying Li, Fenglin Li, Xin Huang, Jiansong Huang, Yunfei Lv, Xia Li, Wenle Ye, Huafeng Wang, Jinghan Wang & Jie Jin

  2. Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, China

    Jiajia Pan, Yungui Wang, Shihui Mao, Qing Ling, Chenying Li, Fenglin Li, Xin Huang, Jiansong Huang, Yunfei Lv, Xia Li, Wenle Ye, Huafeng Wang, Jinghan Wang & Jie Jin

  3. Department of Hematology, the First Affiliated Hospital of University of Science and Technology of China, Anhui, Hefei, China

    Shujuan Huang

  4. Department of Hematology, Affiliated Hangzhou First People’s Hospital, Zhejiang University College of Medicine, Hangzhou, China

    Mengxia Yu

  5. Cancer Center, Zhejiang University, Hangzhou, China

    Jinghan Wang & Jie Jin

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Contributions

PJJ and JJ design the study. PJJ, WYG, and HSJ carried out the study. PJJ and WJH drafted the manuscript. LCY, LQ, LFL, LX, and YWL collected patient samples and helped in the acquisition of data; MSH, YMX, and LYF collected background information; HX, HJS, and WFH performed statistical analysis. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jinghan Wang or Jie Jin.

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Ethics approval and consent to participate

Animal experiment was performed according to the guidelines and SOPs approved by the Department of Science and Technology of Zhejiang Province, China. All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics Committee of the First Affiliated Hospital, Zhejiang University School of Medicine.

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Pan, J., Wang, Y., Huang, S. et al. High expression of BCAT1 sensitizes AML cells to PARP inhibitor by suppressing DNA damage response. J Mol Med 102, 415–433 (2024). https://doi.org/10.1007/s00109-023-02409-1

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