Submitted April 5, 2007
Accepted June 19, 2007
Notch1 co-opts lymphoid enhancer factor 1 for survival of murine T-cell lymphomas
Christina Spaulding, Erica J Reschly, Derek E Zagort, Yumi Yashiro-Ohtani, Levi J Beverly, Anthony Capobianco, Warren S Pear, and Barbara L Kee*
Department of Pathology, The University of Chicago, Chicago, IL, United States
Committee on Cancer Biology, The University of Chicago, Chicago, IL, United States
Dept of Pathology & Lab. Med, Abramson Cancer Research Inst., Institute for Medicine & Engineering, University of Philadelphia, Philadelphia, PA, United States
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, United States
Committees on Immunology & Developmental Biology, The University of Chicago, Chicago, IL, United States
* Corresponding author; email: bkee{at}bsd.uchicago.edu.
Oncogenic Notch1 mutations are found in the majority of 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.
