多发性骨髓瘤（MM）是一种无法治愈的浆细胞恶性疾病，通常采用自体干细胞移植（ASCT）治疗。ASCT的临床反应与DNA修复效率有关。在这里，我们探讨了碱基切除DNA修复（BER）通路在MM对ASCT反应中的作用。在450个临床样本和6个疾病阶段中，BER通路中的基因表达水平在MM发展过程中被发现高度上调。在一个由559名接受ASCT治疗的MM患者组成的独立队列中，BER通路成员MPG和PARP3的表达与总生存期（OS）呈正相关，而PARP1、POLD1和POLD2的表达与OS呈负相关。在一个由356名接受ASCT治疗的MM患者组成的验证队列中，复制了PARP1和POLD2的发现。在从未接受ASCT的MM患者（n=319）中，PARP1和POLD2与OS无关，表明这些基因的预后效应可能取决于治疗。在MM的临床前模型中，当聚合酶（PARP）抑制剂（奥拉帕尼、塔拉索帕尼）与甲氨蝶呤联合使用时，观察到抗肿瘤活性的协同作用。PARP1和POLD2表达的负面预后效应以及PARP抑制对甲氨蝶呤敏感的明显作用可能表明这条通路是ASCT MM患者中的潜在生物标志物。更进一步了解BER通路在MM中的作用对于改善与ASCT相关的治疗策略至关重要。

Multiple Myeloma (MM) is an incurable plasma cell malignancy often treated by autologous stem cell transplant (ASCT). Clinical response to ASCT has been associated with DNA repair efficiency. Here we interrogated the role of the base excision DNA repair (BER) pathway in MM response to ASCT. Across 450 clinical samples and six disease stages, expression levels of genes in the BER pathway were found to be highly upregulated during the development of MM. In a separate cohort of 559 patients with MM treated with ASCT, expression of BER pathway members MPG and PARP3 was positively associated with overall survival (OS) while expression of PARP1, POLD1, and POLD2 was negatively associated with OS. In a validation cohort of 356 patients with MM treated with ASCT, PARP1 and POLD2 findings were replicated. In patients with MM who never received ASCT (n=319), PARP1 and POLD2 were not associated with OS, suggesting that the prognostic effect of these genes may be treatmentdependent. In pre-clinical models of MM, synergy was observed in anti-tumor activity when poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib, talazoparib) were used in combination with melphalan. The negative prognosis associated with PARP1 and POLD2 expression along with the apparent melphalan sensitizing effect of PARP inhibition may suggest this pathway as a potential biomarker in patients with MM in the setting of ASCT. Further understanding of the role of the BER pathway in MM is vital to improve therapeutic strategies related to ASCT.