Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia.
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.
Hodson
Daniel J
DJ
Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK.
Janas
Michelle L
ML
Galloway
Alison
A
Bell
Sarah E
SE
Andrews
Simon
S
Li
Cheuk M
CM
Pannell
Richard
R
Siebel
Christian W
CW
MacDonald
H Robson
HR
De Keersmaecker
Kim
K
Ferrando
Adolfo A
AA
Grutz
Gerald
G
Turner
Martin
M
D000595:Amino Acid Sequence; D000818:Animals; D051817:Butyrate Response Factor 1; D017124:Conserved Sequence; D006801:Humans; D016130:Immunophenotyping; D053208:Kaplan-Meier Estimate; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000254:growth & development / Q000276:immunology*; D014158:Transcription, Genetic; D051816:Tristetraprolin / Q000172:deficiency* / Q000235:genetics / Q000276:immunology
D051817:Butyrate Response Factor 1; C497762:Notch1 protein, mouse; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D051881:Receptor, Notch1; D011948:Receptors, Antigen, T-Cell; D051816:Tristetraprolin; C497553:Zfp36 protein, mouse; C488431:Zfp36l1 protein, mouse