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

Nat Immunol. 2010 Aug;11(8):717-24. doi: 10.1038/ni.1901. Epub 2010 Jul 11.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Notch1 protein, mouse
  • Nuclear Proteins
  • RNA-Binding Proteins
  • Receptor, Notch1
  • Receptors, Antigen, T-Cell
  • Tristetraprolin
  • Zfp36 protein, mouse
  • Zfp36l1 protein, mouse