Machado Caio Bezerra, da Silva Emerson Lucena, Ferreira Wallax Augusto Silva, Pessoa Flávia Melo Cunha de Pinho, de Quadros Andreza Urba, Fantacini Daianne Maciely Carvalho, Furtado Izadora Peter, Rossetti Rafaela, Silveira Roberta Maraninchi, de Lima Sarah Caroline Gomes, Mello Júnior Fernando Augusto Rodrigues, Seabra Aline Damasceno, Moreira Edith Cibelle de Oliveira, de Moraes Filho Manoel Odorico, de Moraes Maria Elisabete Amaral, Montenegro Raquel Carvalho, Ribeiro Rodrigo Monteiro, Khayat André Salim, Burbano Rommel Mário Rodriguez, de Oliveira Edivaldo Herculano Correa, Covas Dimas Tadeu, de Souza Lucas Eduardo Botelho, Moreira-Nunes Caroline de Fátima Aquino
Department of Medicine, Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza 60430-275, CE, Brazil.
Laboratory of Cytogenomics and Environmental Mutagenesis, Environment Section (SAMAM), Evandro Chagas Institute (IEC), Ananindeua 67030-000, PA, Brazil.
Cancers (Basel). 2023 Nov 22;15(23):5510. doi: 10.3390/cancers15235510.
Detection of t(9;22), and consequent fusion, 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 of p190+ 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 of p190+ 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.
检测t(9;22)及其导致的融合，仍然是急性淋巴细胞白血病（ALL）预后较差的一个标志，对酪氨酸激酶抑制剂治疗产生耐药性是这类患者临床治疗中的主要障碍。在本研究中，我们在p190+ ALL模型中研究了靶向聚ADP核糖聚合酶（PARP）的有效性，p190+ ALL是折磨ALL患者的最常见亚型，并证明了使用实验性PARP抑制剂（PARPi）AZD2461作为一种治疗选择，其细胞毒性能力与当前医疗护理的金标准伊马替尼相似。我们利用细胞模型对细胞生长抑制谱、诱导细胞死亡和生物标志物表达调节进行了表征，还通过对所用模型的阵列比较基因组杂交（aCGH）进行了全面的全基因组分析，并进一步验证了PARP1在当地医疗机构的ALL p190+患者样本以及更大规模的在线和现成数据集队列中的差异表达。总体而言，我们证明了PARPi在治疗p190+ ALL细胞模型中的有效性，并且PARP1在患者样本中存在差异表达。我们希望我们的研究结果有助于扩展ALL环境中分子谱的表征，并指导未来临床实践中新型生物标志物检测和药物选择的研究。
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