ABSTRACT
The NSD2 p.E1099K (EK) mutation has been shown to be enriched in patients with relapsed ALL and found to play a role in clonal fitness dependent on the underlying genetic/epigenetic landscape of the cells. To uncover 3D chromatin architecture-related mechanisms underlying drug resistance, we systematically integrated Hi-C, ATAC-seq, RNA-seq and ChIP-seq data from three B-ALL cell lines heterozygous for NSD2 EK (RS4;11, RCH-ACV, SEM) and assessed changes upon knockdown. NSD2 knockdown revealed widespread remodeling of the 3D genome, specifically in terms of compartmentalization. Systematic integration of these datasets revealed significant switches in A/B compartments with a strong bias towards B compartments upon knockdown, suggesting that NSD2 EK plays a prominent role in maintaining A compartments through enrichment of H3K36me2 epigenetic marks. In contrast, we identified few changes in intra-TAD activity suggesting that the NSD2 EK impacts transcriptional changes through a remarkable dependence on compartmentalization. Furthermore, EK-mediated reorganization of compartments highlights the existence of a common core of compacting loci shared across the three cell lines that explain previously described phenotypes as well as serve as targets for therapeutic intervention. This study offers a novel mechanism by which NSD2 EK drives clonal evolution and drug resistance.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵* Jointly supervised this study
CONFLICTS OF INTEREST, The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.