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Molecular and Cellular Biology, January 2006, p. 209-220, Vol. 26, No. 1
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.1.209-220.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Notch Activation Is an Early and Critical Event during T-Cell Leukemogenesis in Ikaros-Deficient Mice

Alexis Dumortier,^1, Robin Jeannet,^1, Peggy Kirstetter,^1,, Eva Kleinmann,^1, MacLean Sellars,^1, Nuno R. dos Santos,² Christelle Thibault,¹ Jochen Barths,¹ Jacques Ghysdael,² Jennifer A. Punt,¹ Philippe Kastner,^1* and Susan Chan^1*

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS-INSERM-ULP, BP10142, 67404 Illkirch, CU Strasbourg,¹ CNRS UMR146, Institut Curie, 91405 Orsay, France²

Received 6 July 2005/ Returned for modification 29 August 2005/ Accepted 3 October 2005

The Ikaros transcription factor is both a key regulator of lymphocyte differentiation and a tumor suppressor in T lymphocytes. Mice carrying a hypomorphic mutation (Ik^L/L) in the Ikaros gene all develop thymic lymphomas. Ik^L/L tumors always exhibit strong activation of the Notch pathway, which is required for tumor cell proliferation in vitro. Notch activation occurs early in tumorigenesis and may precede transformation, as ectopic expression of the Notch targets Hes-1 and Deltex-1 is detected in thymocytes from young Ik^L/L mice with no overt signs of transformation. Notch activation is further amplified by secondary mutations that lead to C-terminal truncations of Notch 1. Strikingly, restoration of Ikaros activity in tumor cells leads to a rapid and specific downregulation of Notch target gene expression and proliferation arrest. Furthermore, Ikaros binds to the Notch-responsive element in the Hes-1 promoter and represses Notch-dependent transcription from this promoter. Thus, Ikaros-mediated repression of Notch target gene expression may play a critical role in defining the tumor suppressor function of this factor.

These authors contributed equally.

Present address: Ludwig Institute for Cancer Research, Epalinges 1066, Switzerland.

Present address: EMBL Monterotondo, Mouse Biology Programme, I-00016 Monterotondo, Italy.

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