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ACUTE LYMPHOBLASTIC LEUKEMIA

Targeting DNA polymerase β elicits synthetic lethality with mismatch repair deficiency in acute lymphoblastic leukemia

Leukemia volume 37, pages 1204–1215 (2023)Cite this article

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Abstract

Mismatch repair (MMR) deficiency has been linked to thiopurine resistance and hypermutation in relapsed acute lymphoblastic leukemia (ALL). However, the repair mechanism of thiopurine-induced DNA damage in the absence of MMR remains unclear. Here, we provide evidence that DNA polymerase β (POLB) of base excision repair (BER) pathway plays a critical role in the survival and thiopurine resistance of MMR-deficient ALL cells. In these aggressive resistant ALL cells, POLB depletion and its inhibitor oleanolic acid (OA) treatment result in synthetic lethality with MMR deficiency through increased cellular apurinic/apyrimidinic (AP) sites, DNA strand breaks and apoptosis. POLB depletion increases thiopurine sensitivities of resistant cells, and OA synergizes with thiopurine to kill these cells in ALL cell lines, patient-derived xenograft (PDX) cells and xenograft mouse models. Our findings suggest BER and POLB’s roles in the process of repairing thiopurine-induced DNA damage in MMR-deficient ALL cells, and implicate their potentials as therapeutic targets against aggressive ALL progression.

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Fig. 1: MMR deficiency causes hypermutation and thiopurine resistance during ALL relapse.
Fig. 2: BER key factor POLB is a potential target for overcoming thiopurine resistance in MMR-deficient ALL cells.
Fig. 3: OA-induced POLB inhibition elicits synthetic lethality with MMR deficiency in ALL cells.
Fig. 4: OA and 6-TG synergize to inhibit the proliferation of MMR-deficient primary ALL cells.
Fig. 5: OA and 6-TG synergize to kill MMR-deficient ALL cells in xenograft mouse models.
Fig. 6: Schematic representation of OA-induced POLB inhibition effect in MMR-deficient ALL.

Data availability

In this study, there were no new datasets generated but re-analysis of existing datasets included in previously published papers as described in Materials and methods. For further information, please contact the corresponding author.

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Acknowledgements

We thank Yu Liu (Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University) for helpful suggestions in clinical data re-analysis; Yan Xu, Yao Chen, Chun-Shuang Ma and Ming-Zhen Tian (Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University) for technical supports and helps. This work was sponsored by grants from National Key R&D Program of China (No. 2021YFA1100800 to B-BSZ), National Natural Science Foundation of China (No. 81970141 to B-BSZ; No. 82100179 to D-PY; No. 82000110 to CT; and No. 82070158 & No. 81870082 to C-WD), Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics (No. 20DZ2260900 to B-BSZ), and Shanghai Sailing Program (No. 21YF1428100 to D-PY).

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Author notes

  1. These authors contributed equally: Ji-Yuan Teng, Ding-Peng Yang, Chao Tang, Hou-Shun Fang.

Authors and Affiliations

  1. Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Ji-Yuan Teng, Ding-Peng Yang, Chao Tang, Hou-Shun Fang, Hui-Ying Sun, Xiao-Meng Li, Fan Yang, Rui-Xue Xia, Fu Fan, Ben-Shang Li, Hui Li, Cai-Wen Duan & Bin-Bing S. Zhou

  2. Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    Yue-Ning Xiang & Jin-Chuan Hu

  3. Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, TN, USA

    Jingjing Liu & Jiyang Yu

  4. State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China

    Fei-Long Meng

  5. Department of Pharmacology and Chemical Biology, School of Basic Medicine and Collaborative Innovation Center for Translational Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Bin-Bing S. Zhou

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Contributions

J-YT, D-PY, CT and H-SF were major contributors to experiments and data analysis. J-YT, D-PY, CT, C-WD and B-BSZ were responsible for interpreting experimental data and writing the paper. H-YS, JL and JY contributed to related bioinformatics analysis. Y-NX, X-ML, FY, R-XX and FF provided reagents and contributed to several in vitro experiments. H-SF and C-WD made major contributions to in vivo experiments. F-LM, J-CH and HL gave helpful suggestions for paper writing. B-SL supplied clinical data of ALL patient samples.

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Correspondence to Ding-Peng Yang, Cai-Wen Duan or Bin-Bing S. Zhou.

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Teng, JY., Yang, DP., Tang, C. et al. Targeting DNA polymerase β elicits synthetic lethality with mismatch repair deficiency in acute lymphoblastic leukemia. Leukemia 37, 1204–1215 (2023). https://doi.org/10.1038/s41375-023-01902-3

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