Mutations in
protein-coding genes are well established as the basis for human
cancer, yet how alterations within noncoding genome, a substantial fraction of which contain cis-regulatory elements (CRE), contribute to
cancer pathophysiology remains elusive. Here, we developed an integrative approach to systematically identify and characterize noncoding regulatory variants with functional consequences in human
hematopoietic malignancies. Combining targeted resequencing of hematopoietic lineage-associated CREs and mutation discovery, we uncovered 1,836 recurrently mutated CREs containing
leukemia-associated noncoding variants. By enhanced CRISPR/dCas9-based CRE perturbation screening and functional analyses, we identified 218 variant-associated oncogenic or
tumor-suppressive CREs in human
leukemia. Noncoding variants at KRAS and PER2 enhancers reside in proximity to
nuclear receptor (NR) binding regions and modulate transcriptional activities in response to NR signaling in
leukemia cells. NR binding sites frequently colocalize with noncoding variants across
cancer types. Hence, recurrent noncoding variants connect enhancer dysregulation with
nuclear receptor signaling in
hematopoietic malignancies. SIGNIFICANCE: We describe an integrative approach to identify noncoding variants in human
leukemia, and reveal cohorts of variant-associated oncogenic and
tumor-suppressive cis-regulatory elements including KRAS and PER2 enhancers. Our findings support a model in which noncoding regulatory variants connect enhancer dysregulation with
nuclear receptor signaling to modulate gene programs in
hematopoietic malignancies.See related commentary by van Galen, p. 646.This article is highlighted in the In This Issue feature, p. 627.