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Noncoding genetic variation in GATA3increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation
| العنوان: | Noncoding genetic variation in GATA3increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation |
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| المؤلفون: | Yang, Hongbo, Zhang, Hui, Luan, Yu, Liu, Tingting, Yang, Wentao, Roberts, Kathryn G., Qian, Mao-xiang, Zhang, Bo, Yang, Wenjian, Perez-Andreu, Virginia, Xu, Jie, Iyyanki, Sriranga, Kuang, Da, Stasiak, Lena A., Reshmi, Shalini C., Gastier-Foster, Julie, Smith, Colton, Pui, Ching-Hon, Evans, William E., Hunger, Stephen P., Platanias, Leonidas C., Relling, Mary V., Mullighan, Charles G., Loh, Mignon L., Yue, Feng, Yang, Jun J. |
| المصدر: | Nature Genetics; 20220101, Issue: Preprints p1-10, 10p |
| مستخلص: | 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 GATA3associated 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 GATA3transcription. This, in turn, reshaped global chromatin accessibility and three-dimensional genome organization, including regions proximal to the ALL oncogene CRLF2. Finally, we showed that GATA3directly regulated CRLF2and 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. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 10614036 15461718 |
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| DOI: | 10.1038/s41588-021-00993-x |