Related Experiment Video
Updated: May 27, 2026
17:59
Derivation of Thymic Lymphoma T-cell Lines from Atm-/- and p53-/- Mice
Published on: April 3, 2011
Sequential mutations in Notch1, Fbxw7, and Tp53 in radiation-induced mouse thymic lymphomas
Kuang-Yu Jen1, Ihn Young Song, Karl Luke Banta
1Department of Pathology, University of California-San Francisco, USA.
Blood
|November 26, 2011
Summary
Activating Notch1 mutations and Fbxw7 deletions in T-cell acute lymphoblastic lymphoma are not mutually exclusive. Notch1 mutations occur first, followed by Fbxw7 deletion, suggesting a specific mutational order in lymphomagenesis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- T-cell acute lymphoblastic lymphoma (T-ALL) frequently involves activating Notch1 mutations and Fbxw7 alterations.
- Fbxw7 normally targets Notch1 for degradation, implying these genetic events should be mutually exclusive in cancer development.
Purpose of the Study:
- To investigate the relationship between Notch1 mutations and Fbxw7 alterations in T-ALL.
- To determine the temporal sequence of these genetic events during lymphomagenesis.
Main Methods:
- Analysis of thymic lymphomas in a radiation-induced Tp53-deficient mouse model.
- Genotyping for Notch1 mutations (specifically in the PEST domain) and Fbxw7 locus alterations (loss of heterozygosity).
- Assessment of Notch1 mutation occurrence in relation to Tp53 status and Fbxw7 haploinsufficiency.
Main Results:
- Concurrent activating Notch1 PEST domain mutations and Fbxw7 single-copy deletions were frequently observed in the same T-ALL tumors.
- Notch1 PEST domain mutations were independent of Tp53 status but were absent in mice with germline Fbxw7 haploinsufficiency.
- These findings indicate that Notch1 PEST domain mutations require intact Fbxw7 expression.
Conclusions:
- The genetic alterations in Notch1 and Fbxw7 are not mutually exclusive in T-ALL.
- A specific temporal order of mutations is suggested: Notch1 PEST domain mutations occur first, followed by Fbxw7 deletion, and then potentially Tp53 loss.
- This sequence provides new insights into the molecular pathogenesis of T-cell acute lymphoblastic lymphoma.
More Related Videos
Related Concept Videos
03:14Notch Signaling Pathway
The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
02:23Abnormal Proliferation
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
02:21Cancers Originate from Somatic Mutations in a Single Cell
Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...