Jayavel Sridhar, Subramanian Manasvini, Kesavan Pradeep Kumar, Jayavel Suresh
Madurai Kamaraj University, Madurai, India.
J Egypt Natl Canc Inst. 2025 Apr 7;37(1):12. doi: 10.1186/s43046-025-00263-5.
Chronic myeloid leukemia (CML) is a kind of leukemia that arises due to the translocation betwixt chromosomes 9 and 22. Philadelphia chromosome is characterized by the BCR::ABL fusion gene, which results from this recombination. It transcribes into active tyrosine kinase variants such as P185, P190, P210, and P230, depending on breakpoint chain variations. The fusion protein, encodes tyrosine kinases with varying exons, resulting in uncontrollable ATP-utilizing downstream signaling activities. Targeted therapy with various tyrosine kinase inhibitors (TKIs) is used to combat BCR::ABL fusion kinases and increase the survival rate of patients. However, the incidence of TKI resistance among CML patients is widely noticed around the world. Hence, an elaborate and accurate understanding of the structural interactions between BCR::ABL encoded tyrosine kinases, which are responsible for sensitivity and resistance, is mandatory for hassle-free targeted therapy. This review is intended to cover the reported structural interactions between BCR::ABL variants and TKI ligands in detail to highlight strategies that may be applied in the near future to overcome the resistance and other cross-reactions.
慢性髓性白血病（CML）是一种由于9号和22号染色体之间易位而引发的白血病。费城染色体的特征是BCR::ABL融合基因，它由这种重组产生。根据断点链变异情况，它转录成活性酪氨酸激酶变体，如P185、P190、P210和P230。融合蛋白编码具有不同外显子的酪氨酸激酶，导致下游ATP利用信号活动失控。使用各种酪氨酸激酶抑制剂（TKIs）进行靶向治疗，以对抗BCR::ABL融合激酶并提高患者生存率。然而，CML患者中TKI耐药的发生率在全球范围内受到广泛关注。因此，详细而准确地了解负责敏感性和耐药性的BCR::ABL编码酪氨酸激酶之间的结构相互作用，对于顺利进行靶向治疗至关重要。本综述旨在详细介绍已报道的BCR::ABL变体与TKI配体之间的结构相互作用，以突出在不久的将来可能应用于克服耐药性和其他交叉反应的策略。
