Detection of t(9;22), and consequentBCR::ABL1fusion, is still a marker of worse prognosis for acute lymphoblastic leukemia (ALL), with resistance to tyrosine-kinase inhibitor therapy being a major obstacle in the clinical practice for this subset of patients. In this study, we investigated the effectiveness of targeting poly-ADP-ribose polymerase (PARP) in a model ofBCR::ABL1p190+ ALL, the most common isoform to afflict ALL patients, and demonstrated the use of experimental PARP inhibitor (PARPi), AZD2461, as a therapeutic option with cytotoxic capabilities similar to that of imatinib, the current gold standard in medical care. We characterized cytostatic profiles, induced cell death, and biomarker expression modulation utilizing cell models, also providing a comprehensive genome-wide analysis through an aCGH of the model used, and further validated PARP1 differential expression in samples of ALL p190+ patients from local healthcare institutions, as well as in larger cohorts of online and readily available datasets. Overall, we demonstrate the effectiveness of PARPi in the treatment ofBCR::ABL1p190+ ALL cell models and that PARP1 is differentially expressed in patient samples. We hope our findings help expand the characterization of molecular profiles in ALL settings and guide future investigations into novel biomarker detection and pharmacological choices in clinical practice.
t(9;22)易位及其导致的BCR::ABL1融合基因检测，目前仍是急性淋巴细胞白血病（ALL）预后不良的标志，而酪氨酸激酶抑制剂治疗耐药性是该亚型患者临床实践中的主要障碍。本研究以ALL患者中最常见的BCR::ABL1 p190+亚型为模型，探讨靶向聚腺苷二磷酸核糖聚合酶（PARP）的治疗效果，并证实实验性PARP抑制剂AZD2461具有与现行标准治疗药物伊马替尼相似的细胞毒性作用。我们通过细胞模型系统评估了细胞生长抑制特征、诱导细胞死亡效应及生物标志物表达调控，同时采用阵列比较基因组杂交技术对模型进行全基因组分析，并在本地医疗机构采集的ALL p190+患者样本及公开可用的大规模数据集中验证了PARP1的差异表达。本研究证实了PARP抑制剂在BCR::ABL1 p190+ ALL细胞模型中的治疗有效性，并揭示PARP1在患者样本中存在差异表达现象。我们期望这些发现能够拓展ALL分子特征谱的认知维度，为未来新型生物标志物检测及临床用药选择提供研究方向。
PARP1 Characterization as a Potential Biomarker forBCR::ABL1p190+ Acute Lymphoblastic Leukemia
肿瘤(癌症)患者之家