Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of BCL11B, a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose BCL11B to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to BCL11B. Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed BCL11B allele and association of BCL11B with activated hematopoietic progenitor cell cis-regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic BCL11B expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia. Significance: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of BCL11B driven by diverse structural alterations, including de novo superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries. This article is highlighted in the In This Issue feature, p. 2659
SUMMARY Early B cell development is characterized by large scale Igh locus contraction prior to V(D)J recombination to facilitate a highly diverse Ig repertoire. However, an understanding of the molecular architecture that mediates locus contraction remains unclear. We have combined high resolution chromosome conformation capture (3C) techniques with 3D DNA FISH to identify three conserved topological sub-domains. Each of these topological folds encompasses a major VH gene family that become juxtaposed in pro-B cells via Mb-scale chromatin looping. The transcription factor Pax5 organizes the sub-domain that spans the VHJ558 gene family. In its absence the J558 VH genes fail to associate with the proximal VH genes, thereby providing a plausible explanation for reduced VHJ558 gene rearrangements in Pax5-deficient pro-B cells. We propose that Igh locus contraction is the cumulative effect of several independently controlled chromatin sub-domains that provide the structural infrastructure to coordinate optimal antigen receptor assembly.
Over 500 genetic loci have been associated with risk of cardiovascular diseases (CVDs); however, most loci are located in gene-distal non-coding regions and their target genes are not known. Here, we generated high-resolution promoter capture Hi-C (PCHi-C) maps in human induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (CMs) to provide a resource for identifying and prioritizing the functional targets of CVD associations. We validate these maps by demonstrating that promoters preferentially contact distal sequences enriched for tissue-specific transcription factor motifs and are enriched for chromatin marks that correlate with dynamic changes in gene expression. Using the CM PCHi-C map, we linked 1999 CVD-associated SNPs to 347 target genes. Remarkably, more than 90% of SNP-target gene interactions did not involve the nearest gene, while 40% of SNPs interacted with at least two genes, demonstrating the importance of considering long-range chromatin interactions when interpreting functional targets of disease loci.
24Over 500 genetic loci have been associated with risk of cardiovascular diseases (CVDs), 25 however most loci are located in gene-distal non-coding regions and their target genes are not known. 26Here, we generated high-resolution promoter capture Hi-C (PCHi-C) maps in human induced 27 pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (CMs) to provide a resource for 28 identifying and prioritizing the functional targets of CVD associations. We validate these maps by 29 demonstrating that promoters preferentially contact distal sequences enriched for tissue-specific 30 transcription factor motifs and are enriched for chromatin marks that correlate with dynamic changes in 31 was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
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