Notch1 promotes survival of E2A-deficient T cell lymphomas through pre-T cell receptor-dependent and -independent mechanisms.
Loss of E2A transcription factor activity or activation of the intracellular form of Notch1 (ICN) leads to the development of leukemia or lymphoma in humans or mice, respectively. Current models propose that ICN functions by suppressing E2A through a pre-T cell receptor (TCR)-dependent mechanism. Here we show that lymphomas arising in E2A(-/-) mice require the activation of Notch1 for their survival and have accumulated mutations in, or near, the Notch1 PEST domain, resulting in increased stability and signaling. In contrast, lymphomas arising in p53(-/-) mice show the activation of Notch1, but no mutations were identified in ICN. The requirement for Notch1 signaling in E2A(-/-) lymphomas cannot be overcome by ectopic expression of pTalpha; however, pTalpha is required for optimal survival and expansion of these cells. Our findings indicate that the activation of Notch1 is an important "second hit" for the transformation of E2A(-/-) T cell lymphomas and that Notch1 promotes survival through pre-TCR-dependent and -independent mechanisms.
Reschly
Erica J
EJ
Department of Pathology, MC1089, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
Spaulding
Christina
C
Vilimas
Tomas
T
Graham
W Vallen
WV
Brumbaugh
Rachel L
RL
Aifantis
Iannis
I
Pear
Warren S
WS
Kee
Barbara L
BL
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency*; D015152:Blotting, Northern; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers; D006801:Humans; D016399:Lymphoma, T-Cell / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051881:Receptor, Notch1 / Q000235:genetics*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency
D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D051881:Receptor, Notch1; D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53; C497761:NOTCH1 protein, human; C407909:TCF3 protein, human