Singh Vivek, Singh Ranjana, Kushwaha Rashmi, Verma Shailendra Prasad, Tripathi Anil Kumar, Mahdi Abbas Ali
Department of Biochemistry, King George's Medical University, Lucknow, India.
Department of Pathology, King George's Medical University, Lucknow, India.
Front Oncol. 2022 Jun 30;12:912942. doi: 10.3389/fonc.2022.912942. eCollection 2022.
Chronic myeloid leukemia (CML) is potentially fatal blood cancer, but there is an unmet need to discover novel molecular biomarkers. The hypothesis of this study aimed to elucidate the relationship of HIF1α with the redox system, Krebs cycles, notch1, and other regulatory proteins to better understand the pathophysiology and clinical relevance in chronic myeloid leukemia (CML) patients, as the molecular mechanism of this axis is still not clear. This study included CML patient samples (n = 60; 60: blood; 10: bone marrow tissues) and compared them with healthy controls (n = 20; blood). Clinical diagnosis confirmed on bone marrow aspiration, marrow trephine biopsy, and BCR/ABL1 translocation. Cases were subclassified into chronic, accelerated, and blast crises as per WHO guidelines. Molecular experiments included redox parameters, DNA fragmentation, Krebs cycle metabolites, and gene expression by RT-PCR/Western blot/LC-MS, PPI (STRING), Pearson correlation, and ROC curve analysis. Here, our findings show that p210/p190BCR/ABL1 translocation is common in all blast crisis phases of CML. Redox factor/Krebs oncometabolite concentrations were high, leading to upregulation and stabilization of HIF1α. HIF1α leads to the pathogenesis in CML cells by upregulating their downstream genes (Notch 2/4/Ikaros/SIRT1/Foxo-3a/p53, etc.). Whereas, downregulated ubiquitin proteasomal and apoptotic factors in CML pateints, can trigger degradation of HIF1α through proline hydroxylation. However, HIF1α showed a negative corelation with the notch1 pathway. Notch1 plays a tumor-suppressive role in CML and might have the potential to be used as a diagnostic marker along with other factors in CML patients. The outcome also revealed that oxidant treatment could not be effective in augmentation with conventional therapy because CML cells can enhance the levels of antioxidants for their survival. HIF1α might be a novel therapeutic target other than BCR/ABL1 translocation.
慢性粒细胞白血病（CML）是一种潜在致命的血液癌症，但发现新型分子生物标志物的需求尚未得到满足。本研究的假设旨在阐明HIF1α与氧化还原系统、三羧酸循环、Notch1及其他调节蛋白之间的关系，以更好地理解慢性粒细胞白血病（CML）患者的病理生理学和临床相关性，因为该轴的分子机制仍不清楚。本研究纳入了CML患者样本（n = 60；60份血液样本；10份骨髓组织样本），并将其与健康对照（n = 20；血液样本）进行比较。通过骨髓穿刺、骨髓活检和BCR/ABL1易位进行临床诊断。根据世界卫生组织指南，病例被分为慢性期、加速期和急变期。分子实验包括氧化还原参数、DNA片段化、三羧酸循环代谢物以及通过RT-PCR/蛋白质免疫印迹/液相色谱-质谱联用、蛋白质-蛋白质相互作用（STRING）、皮尔逊相关性和ROC曲线分析进行基因表达分析。在此，我们的研究结果表明，p210/p190 BCR/ABL1易位在CML的所有急变期均常见。氧化还原因子/三羧酸循环致癌代谢物浓度较高，导致HIF1α上调和稳定。HIF1α通过上调其下游基因（Notch 2/4/Ikaros/SIRT1/Foxo-3a/p53等）导致CML细胞发病。而CML患者中泛素蛋白酶体和凋亡因子下调，可通过脯氨酸羟化触发HIF1α降解。然而，HIF1α与Notch1通路呈负相关。Notch1在CML中发挥肿瘤抑制作用，可能有潜力与CML患者的其他因素一起用作诊断标志物。结果还显示，氧化剂治疗与传统疗法联合使用无效，因为CML细胞可提高抗氧化剂水平以维持生存。HIF1α可能是除BCR/ABL1易位之外的新型治疗靶点。
