Abstract

The development of resistance to apoptosis is a major challenge in treating hematological malignancies, including leukemia. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent that selectively induces apoptosis in many cancer cells by binding to its death receptors, DR4 and DR5. This study investigates the molecular mechanism by which myeloid differentiation, a common process in leukemic cell maturation, affects the sensitivity of leukemic cells to TRAIL-induced cell death. Using established leukemic cell lines, we induced myeloid differentiation and subsequently assessed their susceptibility to TRAIL. Our results demonstrate that differentiated leukemic cells exhibit a significantly increased resistance to TRAIL-induced apoptosis compared to their undifferentiated counterparts. Mechanistically, this resistance correlates with a marked reduction in the surface expression levels of both TRAIL death receptors, DR4 and DR5, following differentiation. Further analysis suggests that the differentiation-induced signaling pathways actively downregulate the transcription or stability of these receptors. These findings highlight a critical link between myeloid maturation and the acquisition of TRAIL resistance, providing a potential therapeutic target to re-sensitize differentiated leukemic cells to TRAIL-based therapies.