Potential therapeutic targets in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is driven by the BCR::ABL fusion oncoprotein, caused by a reciprocal translocation between chromosomes no. 9 and 22, leading to the formation of the Philadelphia chromosome having aberrant tyrosine kinase activity. Tyrosine kinase inhibitors (TKIs) revolutionized the CML treatment and helped patients to achieve a higher survival rate. However, TKI resistance, leukemia stem cell (LSC) persistence, and disease relapse highlight the necessity for alternative treatment strategies. Furthermore, oxidative stress pathways are critical in promoting leukemic development and resistance, offering an emerging avenue for targeted intervention. This review explores several promising therapeutic targets in CML, such as suppressor pathways, autophagy modulation, the BCL-2 family proteins, and microRNAs (miRNAs) modulation. Restoring the function of tumor suppressors, such as PTPRG and p53, may complement current therapies since they are essential in regulating cell proliferation and apoptosis. Tumor suppressors offer the potential to enhance apoptosis, while the precise modulation of autophagy, a complex cellular process with context-dependent roles, can regulate cell survival under therapeutic pressure. The BCL-2 family proteins regulate apoptosis by the mitochondrial intrinsic apoptosis pathway, representing a critical target for overcoming apoptotic resistance in CML cells. Meanwhile, miRNAs emerge as potent modulators of oncogenic and apoptotic pathways by acting as tumor suppressors or oncomiRs, presenting an opportunity for advanced treatment. This review also includes gene editing to target oncogenic drivers or correcting mutations and USP inhibition to overcome resistance. Finally, it concludes by emphasizing the importance of combining these diverse therapeutic approaches with ongoing next-generation TKIs and comprehensive and personalized approaches for CML treatment, offering a path toward deeper remissions and ultimately achieving curative outcomes for CML patients.