E2A proteins enforce a proliferation checkpoint in developing thymocytes

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Abstract
E2A proteins regulate multiple stages of thymocyte development and suppress T‐cell lymphoma. The activity of E2A proteins throughout thymocyte development is modulated by signals emanating from the pre‐TCR and TCR. Here we demonstrate that E2A is required for the complete arrest in both differentiation and proliferation observed in thymocytes with defects in proteins that mediate pre‐TCR signaling, including LAT, Lck and Fyn. We show that E2A proteins are required to prevent the accumulation of TCRβ negative cells beyond the pre‐TCR checkpoint. E2A‐deficient thymocytes also exhibit abnormal cell‐cycle progression prior to pre‐TCR expression. Furthermore, we demonstrate that E47 can act in concert with Bcl‐2 to induce cell‐cycle arrest in vitro . These observations indicate that E2A proteins function during early thymocyte development to block cell‐cycle progression prior to the expression of TCRβ. In addition, these data provide further insight into how deficiencies in E2A lead to T lymphoma.