错配修复（MMR）缺陷已被证实与复发性急性淋巴细胞白血病（ALL）中的噻嗪嘧啶抗性和高突变性有关。然而，在没有MMR的情况下，噻嗪嘧啶诱导的DNA损伤修复机制仍不清楚。在这里，我们提供证据表明，碱基切除修复（BER）通路的DNA聚合酶β（POLB）在MMR缺陷ALL细胞的存活和噻嗪嘧啶抗性中起着关键作用。在这些具有侵袭性耐药ALL细胞中，POLB缺失和其抑制剂齐墩果酸（OA）处理通过增加细胞无环嘌呤/无嘧啶（AP）位点，DNA链断裂和细胞凋亡，与MMR缺陷产生合成致死效应。POLB缺失增加了耐药细胞对噻嗪嘧啶的敏感性，OA与噻嗪嘧啶在ALL细胞系、患者来源的异种移植细胞（PDX）和异种移植小鼠模型中协同杀死这些细胞。我们的发现表明了BER和POLB在修复MMR缺陷ALL细胞中噻嗪嘧啶诱导的DNA损伤中的作用，并暗示它们作为治疗侵袭性ALL进展的潜在靶点。©2023年。作者（们）独家授权Springer Nature Limited。

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.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.