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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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Javier Redondo-Munoz reports financial support was provided by Spain Ministry of Science and Innovation. Raquel Gonzalez-Novo reports financial support was provided by Spain Ministry of Science and Innovation. Manuel Ramirez reports financial support was provided by Pablo Ugarte Association. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and the infiltration of leukemic cells is critical for disease progression and relapse. Nuclear deformability plays a critical role in cancer cell invasion through confined spaces; however, the direct impact of epigenetic changes on the nuclear deformability of leukemic cells remains unclear. Here, we characterized how 3D collagen matrix conditions induced H3K4 methylation in ALL cell lines and clinical samples. We used specific shRNA and chemical inhibitors to target WDR5 (a core subunit involved in H3K4 methylation) and determined that targeting WDR5 reduced the H3K4 methylation induced by the 3D environment and the invasiveness of ALL cells in vitro and in vivo. Intriguingly, targeting WDR5 did not reduce the adhesion or the chemotactic response of leukemia cells, suggesting a different mechanism by which H3K4 methylation might govern ALL cell invasiveness. Finally, we conducted biochemical, and biophysical experiments to determine that 3D environments promoted the alteration of the chromatin, the morphology, and the mechanical behavior of the nucleus in ALL cells. Collectively, our data suggest that 3D environments control an upregulation of H3K4 methylation in ALL cells, and targeting WDR5 might serve as a promising therapeutic target against ALL invasiveness in vivo., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier GmbH.)

Preventing development of childhood B-cell acute lymphoblastic leukemia (B-ALL), a disease with devastating effects, is a longstanding and unsolved challenge. Heterozygous germline alterations in the PAX5 gene can lead to B-ALL upon accumulation of secondary mutations affecting the JAK/STAT signaling pathway. Preclinical studies have shown that this malignant transformation occurs only under immune stress such as exposure to infectious pathogens. Here we show in Pax5+/- mice that transient, early-life administration of clinically relevant doses of ruxolitinib, a JAK1/2 inhibitor, significantly mitigates the risk of B-ALL following exposure to infection; 1 of 29 animals treated with ruxolitinib developed B-ALL versus 8 of 34 untreated mice. Ruxolitinib treatment preferentially targeted Pax5+/- versus wild-type B-cell progenitors and exerted unique effects on the Pax5+/- B-cell progenitor transcriptional program. These findings provide the first in vivo evidence for a potential strategy to prevent B-ALL development., Significance: JAK/STAT inhibition suppresses tumorigenesis in a B-ALL-susceptible mouse model, presenting a novel approach to prevent B-ALL onset., (©2022 The Authors; Published by the American Association for Cancer Research.)