Drug resistance in chronic myeloid leukemia: the involvement of Galectin-1 and Galectin-3.

Tyrosine kinase inhibitors (TKIs) have proven effective in treating chronic myeloid leukemia (CML), but some patients do not benefit from these drugs because TKI-resistant CML cells persist. Galectin-1 (Gal-1) and Galectin-3 (Gal-3) have emerged as critical modulators of CML cell drug resistance. High intracellular Gal-1 levels promote multidrug resistance in vitro by inducing MDR1 expression through p38 MAPK and NF-κB activation, enhancing drug efflux and diminishing anticancer drug efficacy. The effects of Gal-1 have so far been investigated only in in vitro systems; data from in vivo mouse and human studies are not available. Activation of GSK-3β induces Gal-3, which stabilizes anti-apoptotic proteins belonging to the Bcl-2 family and confers resistance to apoptosis-inducing agents in vitro. However, this pathway has not yet been evaluated in CML mouse models or in patients, particularly in the context of TKI resistance mechanisms. Gal-3 is induced by the bone marrow microenvironment (BMME) and promotes AKT and ERK activation to support CML cell proliferation, multidrug resistance (MDR), chemotaxis, and BM lodgment. However, it has not yet been elucidated how Gal-3 is induced by BM stromal cells in CML cells. Furthermore, Gal-3 suppresses the formation of the SERPINA1-albumin complex in vitro, abolishing its growth-inhibitory effects and enhancing paracrine proliferation of CML cells. Although preclinical evidence shows that elevated intracellular Gal-3 protein levels promote drug resistance in CML, these findings have not yet been confirmed at the clinical level. This review underscores that both galectins are critical regulators of CML pathophysiology and highlight their potential as therapeutic targets to overcome TKI resistance.