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 Blood, 1 October 2007, Vol. 110, No. 7, pp. 2650-2658.
Prepublished online as a Blood First Edition Paper on June 21, 2007; DOI 10.1182/blood-2007-04-084202.

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NEOPLASIA

Notch1 co-opts lymphoid enhancer factor 1 for survival of murine T-cell lymphomas

Christina Spaulding1, Erica J. Reschly1,2, Derek E. Zagort1, Yumi Yashiro-Ohtani3, Levi J. Beverly4,5, Anthony Capobianco4,5, Warren S. Pear3, and Barbara L. Kee1,2,6,7

1 Department of Pathology 2 Committee on Cancer Biology, University of Chicago, IL; 3 Department of Pathology and Laboratory Medicine, Abramson Cancer Research Institute, and 4 Institute for Medicine and Engineering, University of Philadelphia, PA; 5 The Wistar Institute, Philadephia, PA; 6 Committee on Immunology 7 Committee on Developmental Biology, University of Chicago, IL

Oncogenic Notch1 mutations are found in most T-lineage acute lymphoblastic leukemias in humans and T-cell lymphomas in mice. However, the mechanism by which Notch1 promotes transformation or maintains malignant cell survival has not been determined fully. Here, we report that expression of the transcription factor lymphoid enhancer factor 1 (Lef1) is Notch dependent in murine T-cell lymphomas in vitro and in vivo, and that the intracellular domain of Notch1 (ICN1) is present at the Lef1 promoter. Lef1 expression is not Notch dependent in primary T-cell progenitors, but Lef1 mRNA is increased by ectopic expression of ICN1 in these cells. We show that Lef1 is required for survival of T-cell lymphoma lines, and that ectopic expression of Lef1 delays lymphoma cell death in the absence of Notch signaling, indicating that Lef1 is an important Notch target in these cells. Therefore, Notch1 co-opts Lef1 during the process of transformation to maintain survival of T-cell lymphomas.


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Related Article in Blood Online:

Lef-1: NOTCHed up in T-cell lymphomas
Fotini Gounari and Marei Dose
Blood 2007 110: 2227. [Full Text] [PDF]





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