The genomic basis of acute leukemia with 3D genomics—The identification of new subtypes: CDX2/UBTF B-ALL and BCL11B-driven leukemia

Abstract

Recent advance in next-generation sequencing technologies has revolutionized the understanding of the genomic basis of leukemia. With whole genome and transcriptome sequencing, most acute lymphoblastic leukemia (ALL) can be defined by genomic subtypes based on the alterations in driver/disease-causing genes. However, most of these subtype-defining alterations are found in the coding regions, and our understanding of non-coding regions is still lacking. Nowadays, the increasing number of facts support the importance of non-coding alterations that may result in epigenomic changes, including putative enhancer generation and chromatin conformation changes. In this review, I will introduce recent development of genomics in leukemia focusing on 3D genomics with HiChIP technology from our recent publications on B-ALL and T/Myeloid Mixed phenotype acute leukemia (MPAL).

CDX2/UBTF B-ALL is the recently defined subtype characterized by unique expression profiles and two concurrent alterations, UBTF::ATXN7L3 fusion and deletion of FLT3 region resulting in deregulation of CDX2. H3K27ac HiChIP showed the mechanism to activate CDX2 by the deletion of FLT3 regions with the use of an adjacent enhancer.

BCL11B-driven leukemia is the subtype of immature leukemia that can transcend lineages, found in early T-cell precursor ALL, MPAL, and acute myeloid leukemia. Aberrant expression of BCL11B in the hematopoietic progenitors is caused by translocations of BCL11B region and active enhancers, or focal amplification to generate neo-enhancer, both of which showed abnormal loops by H3K27ac HiChIP.