Targeting H3K4 methylation as a novel therapeutic strategy against tumor infiltration and nuclear changes of acute lymphoblastic leukemia cells.

Abstract

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and the infiltration of leukemic cells is critical for disease progression and relapse. In spite of the canonical functions of histone methylation in gene regulation, differentiation, and DNA homeostasis; its contribution to the nuclear deformability of migrating leukemic cells remains unclear. Here, we showed that 3D conditions promoted a fast upregulation of H3K4 methylation, bound to transcriptional changes in ALL cells. Furthermore, we demonstrated that targeting WDR5 (a core subunit involved in H3K4 methylation) impaired the invasion of leukemia cells in vitro, and their tissue infiltration in an immunodeficient mouse model. WDR5 expression correlated with other cell receptors involved in leukemia dissemination in clinical samples from ALL patients. Interestingly, blocking WDR5 did not reduce the chemotactic response of leukemia cells, suggesting a different mechanism by which H3K4 methylation might operate at both nuclear and functional level to control ALL cell invasiveness in 3D conditions. We applied biochemical and biophysical approaches to determine that H3K4 methylation induced by 3D conditions was dependent on MLCK activity, and regulated the chromatin compaction and the mechanical nuclear response of leukemia cells in 3D conditions. Collectively, our data revealed that confined conditions provide novel molecular and biophysical mechanisms used by leukemia cells to disseminate, suggesting H3K4 methylation and nuclear mechanical pathways as promising therapeutic targets against ALL infiltration. Highlights3D conditions induce H3K4 methylation and transcriptional changes in ALL cells. Targeting WDR5 and H3K4 methylation blocks ALL cell invasion in vitro 3D conditions and leukemia dissemination in vivo. WDR5 expression correlates with other cell receptors related to leukemia migration in clinical samples from patients with ALL. H3K4 methylation induced by 3D conditions is dependent of MLCK activity and regulates cell movement through 3D environments. Leukemia cells in 3D conditions alter their chromatin compaction and the biomechanical deformability of their nuclei.