Notch1 co-opts lymphoid enhancer factor 1 for survival of murine T-cell lymphomas.
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.
Spaulding
Christina
C
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Reschly
Erica J
EJ
Zagort
Derek E
DE
Yashiro-Ohtani
Yumi
Y
Beverly
Levi J
LJ
Capobianco
Anthony
A
Pear
Warren S
WS
Kee
Barbara L
BL
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002470:Cell Survival; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism*; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D051881:Receptor, Notch1 / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism
D051821:Lymphoid Enhancer-Binding Factor 1; D051881:Receptor, Notch1