| Literature DB >> 35115686 |
Hongbo Yang1,2,3, Hui Zhang4,5,6, Yu Luan1, Tingting Liu1, Wentao Yang4, Kathryn G Roberts7, Mao-Xiang Qian4, Bo Zhang8, Wenjian Yang4, Virginia Perez-Andreu4,9, Jie Xu10, Sriranga Iyyanki10, Da Kuang11, Lena A Stasiak1, Shalini C Reshmi12,13, Julie Gastier-Foster12,13, Colton Smith4, Ching-Hon Pui14, William E Evans4, Stephen P Hunger15, Leonidas C Platanias2, Mary V Relling4, Charles G Mullighan7, Mignon L Loh16, Feng Yue17,18, Jun J Yang19.
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.Entities:
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Year: 2022 PMID： 35115686 DOI： 10.1038/s41588-021-00993-x
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 41.307