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

Hongbo Yang, Hui Zhang, Yu Luan, Tingting Liu, Wentao Yang, Kathryn G. Roberts, Mao xiang Qian, Bo Zhang, Wenjian Yang, Virginia Perez-Andreu, Jie Xu, Sriranga Iyyanki, Da Kuang, Lena A. Stasiak, Shalini C. Reshmi, Julie Gastier-Foster, Colton Smith, Ching Hon Pui, William E. Evans, Stephen P. HungerLeonidas C. Platanias, Mary V. Relling, Charles G. Mullighan, Mignon L. Loh, Feng Yue*, Jun J. Yang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)170-179
Number of pages10
JournalNature Genetics
Volume54
Issue number2
DOIs
StatePublished - Feb 2022

ASJC Scopus subject areas

  • Genetics

Fingerprint

Dive into the research topics of 'Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation'. Together they form a unique fingerprint.

Cite this