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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.

Original publication

DOI

10.1038/ni.1901

Type

Journal article

Journal

Nat Immunol

Publication Date

08/2010

Volume

11

Pages

717 - 724

Keywords

Amino Acid Sequence, Animals, Conserved Sequence, Humans, Immunophenotyping, Kaplan-Meier Estimate, Mice, Mice, Knockout, Molecular Sequence Data, Nuclear Proteins, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, RNA-Binding Proteins, Receptor, Notch1, Receptors, Antigen, T-Cell, Sequence Alignment, T-Lymphocytes, Thymus Gland, Transcription, Genetic, Tristetraprolin