CBX2 shapes chromatin accessibility promoting AML via p38 MAPK signaling pathway

AbstractBackground: The dynamic epigenome and proteins specialized in the interpretation of epigenetic marks criticallycontribute to leukemic pathogenesis but also offer alternative therapeutic avenues. Targeting newly discoveredchromatin readers involved in leukemogenesis may thus provide new anticancer strategies. Accumulating evidencesuggests that the PRC1 complex member CBX2 is overexpressed in solid tumors and promotes cancer cell survival.However, its role in leukemia is still unclear.Methods: We exploited reverse genetic approaches to investigate the role of CBX2 in human leukemic cell lines andex vivo samples. We also analyzed phenotypic effects following CBX2 silencing using cellular and molecular assaysand related functional mechanisms by ATAC-seq and RNA-seq. We then performed bioinformatic analysis of ChIPseqdata to explore the influence of histone modifications in CBX2-mediated open chromatin sites. Lastly, we usedmolecular assays to determine the contribution of CBX2-regulated pathways to leukemic phenotype.Results: We found CBX2 overexpressed in leukemia both in vitro and ex vivo samples compared to CD34+cells.Decreased CBX2 RNA levels prompted a robust reduction in cell proliferation and induction of apoptosis. Similarly,sensitivity to CBX2 silencing was observed in primary acute myeloid leukemia samples. CBX2 suppression increasedgenome-wide chromatin accessibility followed by alteration of leukemic cell transcriptional programs, resulting inenrichment of cell death pathways and downregulation of survival genes. Intriguingly, CBX2 silencing induced epigeneticreprogramming at p38 MAPK-associated regulatory sites with consequent deregulation of gene expression.Conclusions: Our results identify CBX2 as a crucial player in leukemia progression and highlight a potential druggable CBX2-p38 MAPK network in AML.