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Nature Research, Nature Immunology, 8(11), p. 717-724, 2010

DOI: 10.1038/ni.1901

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Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia

Journal article published in 2010 by Daniel J. Hodson ORCID, Michelle L. Janas, Alison Galloway, Sarah E. Bell, Simon Andrews, Cheuk M. Li, Richard Pannell, Christian W. Siebel, H. Robson MacDonald, Kim De Keersmaecker, Adolfo A. Ferrando, Gerald Grutz, Martin Turner ORCID
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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 (TCRbeta). 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.