Mtg16/Eto2 Contributes to Murine T-Cell Development

Abstract

Mtg16/Eto2 is a transcriptional corepressor that is disrupted by t(16;21) in acute myeloid leukemia. Using mice lacking Mtg16, we found that Mtg16 is a critical regulator of T-cell development. Deletion of Mtg16 led to reduced thymocyte development in vivo, and after competitive bone marrow transplantation, there was a nearly complete failure of Mtg16^−/− cells to contribute to thymocyte development. This defect was recapitulated in vitro as Mtg16^−/− Lineage⁻/Sca1⁺/c-Kit⁺ (LSK) cells of the bone marrow or DN1 cells of the thymus failed to produce CD4⁺/CD8⁺ cells in response to a Notch signal. Complementation of these defects by reexpressing Mtg16 showed that 3 highly conserved domains were somewhat dispensable for T-cell development but required the capacity of Mtg16 to suppress E2A-dependent transcriptional activation and to bind to the Notch intracellular domain. Thus, Mtg16 integrates the activities of signaling pathways and nuclear factors in the establishment of T-cell fate specification.

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Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01458-10.

ACKNOWLEDGMENTS

We thank the members of the Hiebert lab and Utpal Dave and Susan Cleveland for helpful discussions. We thank Jonathan Keller (NCI) for the Id1 and Id2 expression plasmids, Juan-Carlos Zuniga-Pfluker (University of Toronto) for the OP9-DL1 cells, Robert Roeder (The Rockefeller University) for the E-box luciferase plasmid, and T. Ikawa and C. Murre (UCSD) for the E47-ER and Notch gene expression data sets. We thank the Vanderbilt-Ingram Cancer Center (P30CA68485) and the Vanderbilt Digestive Diseases Research Center (5P30DK58404) for support and the use of shared resources, including flow cytometry, functional genomics/microarrays, transgenic/embryonic stem cells, and human tissue acquisition and pathology.

This work was supported by National Institutes of Health (NIH) grants R01-CA64140 (S.W.H.), R01-HL088494 (S.W.H.), and F30 HL093993 (A.H.).