Dynamic 3D chromosomal landscapes in acute leukemia [WGS]

Background: Disruptions of 3D chromatin architecture can alter the activity of topologically associated domains (TADs), rewire enhancer-promoter interactions and thus significantly impact gene regulatory programs. Recently, such disruptions have been implicated in tumorigenesis, highlighting the need for a deeper understanding of their detailed role. Methods: T-ALL primary samples and prototypical cell lines as well as healthy T cell samples were profiled by in-situ Hi-C, RNA-Seq, CTCF ChIP-Seq and suuported by matching WGS of three primary T-ALL samples. Data was subsequently integrated. Results: Our studies showed that the genome of leukemia cells does not display global changes in TAD structures but presents local changes in selected TAD boundaries as well as alterations of intra-TAD activity which are associated with changes in gene expression of key oncogenes and tumor suppressors, strong correlation with CTCF-mediated insulation and enhancer activity. Finally, we showed that 3D interactions on selected loci can be partially corrected pharmacologically, potentially accounting for the anti-leukemogenic effects of these drugs. Conclusions: Our studies underscore the need for further investigation of factors that rewire long range interactions especially during tumorigenesis, as they could be targets for pharmacological targeting. Overall design: Primary samples and prototypical cell lines of T cell acute lymphoblastic leukemia (T-ALL) as well as healthy T cell counterparts from three different donors were collected. Primary T-ALL cells isolated from the peripheral blood of T-ALL patients were xenogroafted in immunocompromised NOD SCID gamma mice (NSG) . Following xenograft and when the tumor burden in pheripheral blood reached 80% the mice were the spleen was harvested and splenocytes were used for the Whole Genome Sequencing (WGS) analysis.