GSE193383
WDR5 activity regulates nuclear changes and migration of acute lymphoblastic leukemia cells across confined spaces.
Purpose: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and  infiltration of leukemic cells is critical for disease progression and relapse. In spite of the  canonical functions of epigenetics in transcription and DNA homeostasis, its contribution to  the nuclear deformability of migrating leukemic cells remains unclear. The objective was to  evaluate the role of WDR5 (a core subunit of the histone H3K4 methyltransferases) during  leukemia cell migration.  Experimental design: We used ALL cell lines and primary samples from patients to study  their response and migration in 3D environments and how they extravasate in a mouse  xenograft model. We also performed, biophysical, transcriptional and ChIP-sequencing  analyses to determine the mechanism by which WDR5 controls ALL progression.  Results: We observed that WDR5 activity is critical for ALL cell invasion into 3D collagen  matrices. Notably, blocking WDR5 activity also decreased the extravasation of ALL cells in  an in vivo model. We identified that 3D constrained conditions promoted H3K4 methylation  in ALL cells that altered the global chromatin configuration and transcriptional changes  related to cell cycle and DNA replication. WDR5 inhibition did not impair cell adhesion or  cell response to chemokines; but we demonstrated that 3D conditions affected the  deformation and biophysical behavior of the nucleus in ALL cells.  Conclusions: We conclude that confined conditions have a fundamental role in ALL cell  biology and provide novel molecular and biophysical mechanisms used by leukemia cells to  disseminate. Targeting WDR5 might be a promising therapeutic strategy against ALL  infiltration and dissemination. Overall design: 3 replicates of CCRF-CEM control and cultured in 3D conditions for 3 hours were used for chromatin immunoprecipitation of H3K4me3 and their DNA was extracted and sequenced. DNA from a control sample of the ChIP and from cells before de ChIP (input) was also sequenced.