Targeting DNA polymerase β elicits synthetic lethality with mismatch repair deficiency in acute lymphoblastic leukemia.
Ji-Yuan TengDing-Peng YangChao TangHou-Shun FangHui-Ying SunYue-Ning XiangXiao-Meng LiFan YangRui-Xue XiaFu FanJingJing LiuJiyang YuJin-Chuan HuBen-Shang LiHui LiFei-Long MengCai-Wen DuanBin-Bing S ZhouPublished in: Leukemia (2023)
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.
Keyphrases
- induced apoptosis
- cell cycle arrest
- acute lymphoblastic leukemia
- dna damage
- oxidative stress
- endoplasmic reticulum stress
- cell death
- signaling pathway
- drug delivery
- circulating tumor
- acute myeloid leukemia
- transcription factor
- mouse model
- cell free
- cell proliferation
- knee osteoarthritis
- cancer therapy
- single molecule
- hodgkin lymphoma
- drug induced
- diabetic rats