NDLI: Enhanced Notch Activation Is Advantageous but Not Essential for T Cell Lymphomagenesis in Id1 Transgenic Mice

Content Provider	PubMed Central
Author	Wang, Hong-cheng Peng, Vincent Zhao, Ying Sun, Xiao-hong
Editor	Swarbrick, Alexander
Copyright Year	2012
Abstract	T cell lymphoblastic leukemia (T-ALL) is known to be associated with chromosomal abnormalities that lead to aberrant expression of a number of transcription factors such as TAL1, which dimerizes with basic helix-loop-helix (bHLH) E proteins and inhibits their function. Activated Notch receptors also efficiently induce T cell leukemogenesis in mouse models. Interestingly, gain-of-function mutations or cryptic transcription initiation of the Notch1 gene have been frequently found in both human and mouse T-ALL. However, the correlations between these alterations and overall Notch activities or leukemogenesis have not been thoroughly evaluated. Therefore, we made use of our collection of T cell lymphomas developed in transgenic mice expressing Id1, which like TAL1, inhibits E protein function. By comparing expression levels of Notch target genes in Id1-expressing tumors to those in tumors induced by a constitutively active form of Notch1, N1C, we were able to assess the overall activities of Notch pathways and conclude that the majority of Id1-expressing tumors had elevated Notch function to a varying degree. However, 26% of the Id1-expressing tumors had no evidence of enhanced Notch activation, but that did not delay the onset of tumorigenesis. Furthermore, we examined the genetic or epigenetic alterations thought to contribute to ligand-independent activation or protein stabilization of Notch1 and found that some of the Id1-expressing tumors acquired these changes, but they are not uniformly associated with elevated Notch activities in Id1 tumor samples. In contrast, N1C-expressing tumors do not harbor any PEST domain mutations nor exhibit intragenic transcription initiation. Taken together, it appears that Notch activation provides Id1-expressing tumor cells with selective advantages in growth and survival. However, this may not be absolutely essential for lymphomagenesis in Id1 transgenic mice and additional factors could also cooperate with Id1 to induce T cell lymphoma. Therefore, a broad approach is necessary in designing T-ALL therapy.
Related Links	http://dx.doi.org/10.1371/journal.pone.0032944
Starting Page	32944
File Format	PDF
ISSN	19326203
e-ISSN	19326203
Journal	PLoS ONE
Issue Number	2
Volume Number	7
Language	English
Publisher	Public Library of Science
Publisher Date	2012-02-01
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Agricultural and Biological Sciences(all) Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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