Noncoding Genetic Variation in GATA3 Increases Acute Lymphoblastic Leukemia Risk Through Local and Global Changes in Chromatin Conformation

Overview

Journal Nat Genet

Specialty Genetics

Date 2022 Feb 4

PMID 35115686

Authors

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 Hunger

Leonidas C Platanias

Mary V Relling

Charles G Mullighan

Mignon L Loh

Feng Yue

Jun J Yang

Affiliations

Soon will be listed here.

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.

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