期刊
NATURE IMMUNOLOGY
卷 11, 期 8, 页码 717-U84出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.1901
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- Cancer Research UK
- Addenbrooke's Charitable Trust
- Medical Research Council
- Biotechnology and Biological Sciences Research Council [BB/C506121/1]
- US National Institutes of Health [R01CA120196, R01CA129382]
- European College of Obstetrics and Gynaecology tumor bank [U24 CA114737]
- Leukemia & Lymphoma Society
- Fonds voor Wetenschappelijk Onderzoek-Vlaanderen
- Belgian American Educational Foundation
- BBSRC [BBS/E/B/0000H190, BB/F02066X/1] Funding Source: UKRI
- MRC [G0601618] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/C506121/1, BBS/E/B/0000M983, BBS/E/B/0000H190, BB/F02066X/1] Funding Source: researchfish
- Medical Research Council [G0601618] Funding Source: researchfish
ZFP36L1 and ZFP36L2 are RNA-binding proteins (RBPs) that interact with AU-rich elements in the 3' untranslated region of mRNA, which leads to mRNA degradation and translational repression. Here we show that mice that lacked ZFP36L1 and ZFP36L2 during thymopoiesis developed a T cell acute lymphoblastic leukemia (T-ALL) dependent on the oncogenic transcription factor Notch1. Before the onset of T-ALL, thymic development was perturbed, with accumulation of cells that had passed through the beta-selection checkpoint without first expressing the T cell antigen receptor beta-chain (TCR beta). Notch1 expression was higher in untransformed thymocytes in the absence of ZFP36L1 and ZFP36L2. Both RBPs interacted with evolutionarily conserved AU-rich elements in the 3' untranslated region of Notch1 and suppressed its expression. Our data establish a role for ZFP36L1 and ZFP36L2 during thymocyte development and in the prevention of malignant transformation.
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