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

DJ Hodson, ML Janas, A Galloway, SE Bell… - Nature …, 2010 - nature.com
DJ Hodson, ML Janas, A Galloway, SE Bell, S Andrews, CM Li, R Pannell, CW Siebel…
Nature immunology, 2010nature.com
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 β-selection checkpoint …
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 β-selection checkpoint without first expressing the T cell antigen receptor β-chain (TCRβ). 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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