Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation

A germline variant associated with acute lymphoblastic leukemia activates an enhancer element resulting in increased GATA3 expression, altered chromatin accessibility and changes in three-dimensional genome organization. Inherited noncoding genetic variants confer significant disease susceptibility to childhood acute lymphoblastic leukemia (ALL) but the molecular processes linking germline polymorphisms with somatic lesions in this cancer are poorly understood. Through targeted sequencing in 5,008 patients, we identified a key regulatory germline variant in GATA3 associated with Philadelphia chromosome-like ALL (Ph-like ALL). Using CRISPR-Cas9 editing and samples from patients with Ph-like ALL, we showed that this variant activated a strong enhancer that upregulated GATA3 transcription. This, in turn, reshaped global chromatin accessibility and three-dimensional genome organization, including regions proximal to the ALL oncogene CRLF2. Finally, we showed that GATA3 directly regulated CRLF2 and potentiated the JAK-STAT oncogenic effects during leukemogenesis. Taken together, we provide evidence for a distinct mechanism by which a germline noncoding variant contributes to oncogene activation, epigenetic regulation and three-dimensional genome reprogramming.

Automated summary

This study identifies a germline variant associated with acute lymphoblastic leukemia (ALL) that activates an enhancer element leading to increased GATA3 expression, altered chromatin accessibility, and changes in three-dimensional genome organization. The variant is found to regulate the activation of the oncogene CRLF2 through direct regulation of GATA3, potentiating the oncogenic effects during leukemogenesis.