The hallmark of Chronic Myeloid Leukemia (CML) is Philadelphia chromosome t(9:22), which leads to formation of BCR-ABL1 fusion oncogene. BCR-ABL1 induces genetic instability, causing the progression of chronic myeloid leukemia (CML) from the manageable Chronic Phase (CP-CML) to the accelerated phase (AP-CML) and ultimately to the lethal blast crisis (BC-CML). The precise mechanism responsible for CML progression are not well comprehended, and there is a lack of specific molecular biomarkers for advanced phase CML. Mutations in transcription factors (TFs) have a significant role in cancer initiation, relapses, invasion, metastasis, and resistance to anti-cancer drugs. Recently, our group reported association of a novel transcription factor, ZNF208, with CML progression and there was a dire need for clinical validation of this novel biomarker. Therefore, the aim of this study was to clinically validate mutated ZNF208 as a novel biomarker for CML progression in a larger cohort of AP- and BC-CML patients using control-case studies. A total of 73 CML patients (N=73) from King Saud University Medical City Riyadh and King Abdulaziz National Guard Hospital, Al-Ahsa, Saudi Arabia were enrolled in the study (2020-2023) , with the experimental group (cases) consisting of patients AP-CML (n=20) and BC-CML (n=12). The controls consisted of age/sex matched CP-CML (n=41). The study was approved by Research Ethics Committees of participating institutes and all patients provided informed consent for the study. Clinical evaluations for patients were conducted according to the guidelines established by the European LeukemiaNet in 2020. Targeted resequencing of ZNF 208 was employed using Illumina NextSeq500 instrument (Illumina, San Diego, CA, USA) and mutations confirmed using Sanger sequencing. Both next generation sequencing as well as Sanger sequencing identified a novel missense mutation (c.64G>A) in novel ZNF208 . in 56 (93.3) and12 (100) CP-, AP- and BC-CML patients respectively, while in none (0%) of CP-CML patients or healthy controls from genomic databases (p=0.0001). Therefore, our studies show that ZNF208 mutation (c.64G>A) is novel and very specific biomarker for AP-and BC-CML patients. ZNF208 and other such proteins may cause carcinogenesis by interacting with KAP-1 repressor to silence many target genes and thus may prove to be novel drug targets as well. Therefore, we recommend carrying out prospective clinical trials for further clinical validation of this biomarker for its utilization in clinical decision, investigating its precise role in cancer pathogenesis and investigate its potential for novel drug target in advanced phase CML patients.

中文翻译：

---

突变 ZNF208 作为慢性粒细胞白血病致命急变的新型生物标志物的临床验证的回顾性病例对照研究

慢性粒细胞白血病 (CML) 的标志是费城染色体 t(9:22)，它导致 BCR-ABL1 融合癌基因的形成。BCR-ABL1 诱导遗传不稳定，导致慢性粒细胞白血病 (CML) 从可控制的慢性期 (CP-CML) 进展到加速期 (AP-CML)，并最终发展为致命的急变期 (BC-CML)。CML 进展的确切机制尚不清楚，并且缺乏晚期 CML 的特异性分子生物标志物。转录因子（TF）突变在癌症发生、复发、侵袭、转移和抗癌药物耐药性中发挥重要作用。最近，我们的小组报告了一种新型转录因子 ZNF208 与 CML 进展的关联，迫切需要对这种新型生物标志物进行临床验证。因此，本研究的目的是通过对照病例研究，在更大的 AP-和 BC-CML 患者队列中临床验证突变 ZNF208 作为 CML 进展的新型生物标志物。本研究（2020-2023年）纳入了来自利雅得沙特国王大学医学城和沙特阿拉伯阿卜杜勒阿齐兹国王国民警卫队医院的73名CML患者（N=73），实验组（例）包括AP-CML (n=20) 和 BC-CML (n=12) 患者。对照组由年龄/性别匹配的 CP-CML (n=41) 组成。该研究得到了参与机构的研究伦理委员会的批准，所有患者都对该研究提供了知情同意书。根据2020年欧洲白血病网制定的指南对患者进行临床评估。使用Illumina NextSeq500仪器（Illumina，圣地亚哥，加利福尼亚州，美国）对ZNF 208进行靶向重测序，并使用Sanger测序确认突变。下一代测序和桑格测序均在新型 ZNF208 中鉴定出新型错义突变 (c.64G>A)。基因组数据库中分别有 56 (93.3) 和 12 (100) 名 CP-、AP- 和 BC-CML 患者出现这种情况，而 CP-CML 患者或健康对照中则没有 (0%) (p=0.0001)。因此，我们的研究表明，ZNF208 突变 (c.64G>A) 是 AP-和 BC-CML 患者的新型且非常特异的生物标志物。ZNF208 和其他此类蛋白质可能通过与 KAP-1 阻遏物相互作用沉默许多靶基因而导致癌变，因此也可能被证明是新的药物靶点。因此，我们建议开展前瞻性临床试验，进一步临床验证该生物标志物在临床决策中的应用，研究其在癌症发病机制中的精确作用，并研究其作为晚期 CML 患者新药物靶点的潜力。