Dual effect of targeting LSD1 on the invasiveness and the mechanical response of acute lymphoblastic leukemia cells

Epigenetic alterations are hallmarks of cancer, with histone modifiers playing critical roles in gene transcription, DNA homeostasis, and other nuclear functions. Lysine-specific demethylase 1 (LSD1), a key regulator of H3K4 methylation, has emerged as a promising pharmacological target in cancer treatment, including leukemia. Acute lymphoblastic leukemia (ALL), the most common pediatric cancer, remains a significant therapeutic challenge due to limited understanding of how epigenetic therapy impacts leukemia dissemination. In this study, we demonstrate that targeting LSD1 enhances the invasive capacity of ALL cells, inducing an elongated, invasive phenotype and increasing nuclear deformability. Using a 3D matrix model, LSD1 inhibition promoted ALL cell invasion without significantly affecting the cell cycle progression or apoptosis under the tested conditions. Interestingly, LSD1 targeting reduced ALL cell spreading and tissue colonization in vivo, suggesting differential effects depending on the cellular context. Our findings indicate that LSD1 inhibition impairs chemotactic responses and transendothelial migration, key processes for extravasation and in vivo invasiveness. These results reveal a dual role for LSD1 in leukemia cell migration: promoting invasiveness in 3D environments while reducing extravasation and chemotaxis in vivo. This dual effect underscores the importance of cellular context in determining therapeutic outcomes and the development of strategies targeting specific stages of leukemia dissemination.