Abstract

The tumor microenvironment, particularly the formation of multicellular aggregates, is a critical factor contributing to therapeutic resistance in acute myeloid leukemia (AML). This study investigates the cellular and molecular changes in the AML cell line THP-1 when cultured as cell aggregates in vitro, focusing on their resistance to TNF-related apoptosis-inducing ligand (TRAIL). We observed that the formation of these aggregates is associated with the appearance of signs of monocyte-like differentiation, a process highly relevant to membrane and cell biology due to changes in cell-cell adhesion and surface receptor expression. Concurrently, the aggregated THP-1 cells acquired a distinct pro-inflammatory phenotype, characterized by altered cytokine production and signaling pathways. Crucially, this differentiation and pro-inflammatory shift correlated with a significant increase in TRAIL resistance. Mechanistically, this suggests that the microenvironmental cues within the cell aggregates drive a phenotypic switch in AML cells, linking differentiation and inflammation to a survival advantage against apoptosis-inducing agents. These findings underscore the importance of the cellular aggregation state in AML pathogenesis and highlight the pro-inflammatory phenotype as a potential therapeutic target to overcome TRAIL resistance in AML.