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SCL and LMO1 alter thymocyte differentiation: inhibition of E2A-HEB function and pre-Tα chain expression

Nature Immunology volume 1, pages 138–144 (2000)Cite this article

Abstract

Cooperation between the stem cell leukemia (SCL) transcription factor and its nuclear partners LMO1 or LMO2 induces aggressive T cell acute lymphoblastic leukemia when inappropriately expressed in T cells. This study examined the cellular and molecular targets of the SCL-LMO complex at the pre-leukemic stage. We show that SCL and its partners are coexpressed in the most primitive thymocytes. Maturation to the pre-T cell stage is associated with a down-regulation of SCL and LMO1 and LMO2, and a concomitant up-regulation of E2A and HEB expression. Moreover, enforced expression of SCL-LMO1 inhibits T cell differentiation and recapitulates a loss of HEB function, causing a deregulation of the transition checkpoint from the CD4−CD8− to CD4+CD8+ stages. Finally, we identify the gene encoding pTα as a downstream target of HEB that is specifically repressed by the SCL-LMO complex.

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Figure 1: SCL and its partners are coexpressed in primitive DN thymocytes.
Figure 2: Consequences of SCL-LMO1 expression in the thymus.
Figure 3: Increased apoptosis and decreased cell cycling at the DN to DP transition.
Figure 4: The SCL-LMO complex represses the expression of pTα.
Figure 5: Specific repression of pTa enhancer by the SCL-LMO complex.
Figure 6: SCL-LMO1 expression down-regulates CD4 expression.

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Acknowledgements

We thank N. Tessier for assistance with cell sorting and M. Ratcliffe and A. Veillette for reading the manuscript. This work was supported in part by a grant from the Medical Research Council of Canada and a postdoctoral fellowship from the French Medical Research Foundation and the Fonds de la recherche en santé du Québec (S.H.).

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Authors and Affiliations

  1. Clinical Research Institute of Montréal, Montréal, H2W1R7 , Québec, Canada

    Sabine Herblot, Ann-Muriel Steff, Patrice Hugo & Trang Hoang

  2. Procrea BioSciences Inc., Montréal, H4P 2R2, Québec, Canada

    Ann-Muriel Steff & Patrice Hugo

  3. Genetics Department, Division of Clinical Science, Medicine Branch, National Cancer Institute, Gaithersburg, 20877, MD , USA

    Peter D. Aplan

  4. Departments of Pharmacology, Biochemistry and the Molecular Biology Program, University of Montréal, H3C 3J7, Québec, Canada

    Trang Hoang

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  1. Sabine Herblot
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Correspondence to Trang Hoang.

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Herblot, S., Steff, AM., Hugo, P. et al. SCL and LMO1 alter thymocyte differentiation: inhibition of E2A-HEB function and pre-Tα chain expression. Nat Immunol 1, 138–144 (2000). https://doi.org/10.1038/77819

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