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Characterization of two distinct lymphoproliferative diseases caused by ectopic expression of the Notch ligand DLL4 on T cells.
- Source :
-
PloS one [PLoS One] 2013 Dec 27; Vol. 8 (12), pp. e84841. Date of Electronic Publication: 2013 Dec 27 (Print Publication: 2013). - Publication Year :
- 2013
-
Abstract
- Notch signaling is essential for the development of T cell progenitors through the interaction of NOTCH1 receptor on their surface with the ligand, Delta-like 4 (DLL4), which is expressed by the thymic epithelial cells. Notch signaling is quickly shut down once the cells pass β-selection, and CD4/CD8 double positive (DP) cells are unresponsive to Notch. Over the past two decades a number of papers reported that over-activation of Notch signaling causes T cell acute lymphoblastic leukemia (T-ALL), a cancer that prominently features circulating monoclonal CD4/CD8 double positive T cells in different mouse models. However, the possible outcomes of Notch over-activation at different stages of T cell development are unknown, and the fine timing of Notch signaling that results in T-ALL is poorly understood. Here we report, by using a murine model that ectopically expresses DLL4 on developing T cells, that the T-ALL onset is highly dependent on a sustained Notch activity throughout the DP stage, which induces additional mutations to further boost the signaling. In contrast, a shorter period of Notch activation that terminates at the DP stage causes a polyclonal, non-transmissible lymphoproliferative disorder that is also lethal. These observations resolved the discrepancy of previous papers on DLL4 driven hematological diseases in mice, and show the critical importance of the timing and duration of Notch activity.
- Subjects :
- Adaptor Proteins, Signal Transducing
Animals
CD4-Positive T-Lymphocytes pathology
CD8-Positive T-Lymphocytes pathology
Calcium-Binding Proteins
Intracellular Signaling Peptides and Proteins genetics
Membrane Proteins genetics
Mice
Mice, Transgenic
Neoplasms, Experimental genetics
Neoplasms, Experimental pathology
Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
Receptors, Notch genetics
Receptors, Notch metabolism
CD4-Positive T-Lymphocytes metabolism
CD8-Positive T-Lymphocytes metabolism
Gene Expression Regulation, Leukemic
Intracellular Signaling Peptides and Proteins biosynthesis
Membrane Proteins biosynthesis
Neoplasms, Experimental metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 24386421
- Full Text :
- https://doi.org/10.1371/journal.pone.0084841