MLL-fusions shape distinct chromatin landscapes

Fusion of the N-terminus of mixed-lineage-leukemia (MLL) gene with various partner genes drives a group of acute lymphoblastic leukemia (ALL). Although all fusion proteins retain the same MLL N-terminal domains mediating chromatin binding, ALL harboring different types of MLL-fusion displays transcriptional heterogeneity, the underlying mechanisms and biological consequences of which are unknown. We compared the genome-wide chromatin binding patterns and the associated epigenetic status of MLL-Af4 versus MLL-AF9 in isogenic ALL cells derived from human CD34+ hematopoietic stem and progenitor cells (HSPCs). We demonstrated that the fusion type-specific chromatin binding and disparate epigenetic regulation contributed to the different gene expression patterns distinguishing the two types of ALL.