Lacoste Sandrine, Bhatia Smita, Chen Yanjun, Bhatia Ravi, O'Connor Timothy R
Department of Cancer Biology, Beckman Research Institute, Duarte, California, United States of America.
Institute for Cancer Outcomes and Survivorship, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
PLoS One. 2017 Feb 16;12(2):e0171473. doi: 10.1371/journal.pone.0171473. eCollection 2017.
Patients who undergo autologous hematopoietic stem cell transplantation (aHCT) for treatment of a relapsed or refractory lymphoma are at risk of developing therapy related- myelodysplasia/acute myeloid leukemia (t-MDS/AML). Part of the risk likely resides in inherent interindividual differences in their DNA repair capacity (DRC), which is thought to influence the effect chemotherapeutic treatments have on the patient's stem cells prior to aHCT. Measuring DRC involves identifying small differences in repair proficiency among individuals. Initially, we investigated the cell model in healthy individuals (primary lymphocytes and/or lymphoblastoid cell lines) that would be appropriate to measure genetically determined DRC using host-cell reactivation assays. We present evidence that interindividual differences in DRC double-strand break repair (by non-homologous end-joining [NHEJ] or single-strand annealing [SSA]) are better preserved in non-induced primary lymphocytes. In contrast, lymphocytes induced to proliferate are required to assay base excision (BER) or nucleotide excision repair (NER). We established that both NHEJ and SSA DRCs in lymphocytes of healthy individuals were inversely correlated with the age of the donor, indicating that DSB repair in lymphocytes is likely not a constant feature but rather something that decreases with age (~0.37% NHEJ DRC/year). To investigate the predictive value of pre-aHCT DRC on outcome in patients, we then applied the optimized assays to the analysis of primary lymphocytes from lymphoma patients and found that individuals who later developed t-MDS/AML (cases) were indistinguishable in their DRC from controls who never developed t-MDS/AML. However, when DRC was investigated shortly after aHCT in the same individuals (21.6 months later on average), aHCT patients (both cases and controls) showed a significant decrease in DSB repair measurements. The average decrease of 6.9% in NHEJ DRC observed among aHCT patients was much higher than the 0.65% predicted for such a short time frame, based on ageing results for healthy individuals.
接受自体造血干细胞移植（aHCT）治疗复发或难治性淋巴瘤的患者有发生治疗相关骨髓增生异常综合征/急性髓系白血病（t-MDS/AML）的风险。部分风险可能在于其DNA修复能力（DRC）存在个体差异，这被认为会影响化疗在aHCT前对患者干细胞的作用效果。测量DRC涉及识别个体间修复熟练度的微小差异。最初，我们研究了健康个体（原代淋巴细胞和/或淋巴母细胞系）中适合使用宿主细胞再激活试验测量基因决定的DRC的细胞模型。我们提供的证据表明，DRC双链断裂修复（通过非同源末端连接[NHEJ]或单链退火[SSA]）的个体差异在未诱导的原代淋巴细胞中保存得更好。相比之下，诱导增殖的淋巴细胞则用于检测碱基切除修复（BER）或核苷酸切除修复（NER）。我们确定健康个体淋巴细胞中的NHEJ和SSA DRC均与供体年龄呈负相关,这表明淋巴细胞中的双链断裂修复可能不是一个恒定的特征，而是会随着年龄增长而下降（约每年下降0.37%的NHEJ DRC）。为了研究aHCT前DRC对患者预后的预测价值，我们随后将优化后的试验应用于淋巴瘤患者原代淋巴细胞的分析，发现后来发生t-MDS/AML的个体（病例组）与从未发生t-MDS/AML的对照组在DRC方面没有差异。然而，当在同一患者aHCT后不久（平均21.6个月后）检测DRC时，aHCT患者（病例组和对照组）的双链断裂修复测量值均显著下降。aHCT患者中观察到的NHEJ DRC平均下降6.9%，远高于根据健康个体衰老结果预测的在如此短时间内下降0.65%。
