PUBLICATION
NOTCH1-induced T-cell leukemia in transgenic zebrafish
- Authors
- Chen, J., Jette, C., Kanki, J.P., Aster, J.C., Look, A.T., and Griffin, J.D.
- ID
- ZDB-PUB-070210-33
- Date
- 2007
- Source
- Leukemia 21(3): 462-471 (Journal)
- Registered Authors
- Chen, Jihua, Jette, Cicely A., Kanki, John, Look, A. Thomas
- Keywords
- Notch, bcl2, T-ALL, zebrafish
- MeSH Terms
-
- Female
- Signal Transduction
- Recombinant Fusion Proteins/physiology
- Gamma Rays
- Apoptosis
- Radiation Chimera
- Neoplasm Transplantation
- Receptor, Notch1/genetics
- Receptor, Notch1/physiology*
- Oncogenes
- Leukemia-Lymphoma, Adult T-Cell/etiology*
- Leukemia-Lymphoma, Adult T-Cell/genetics
- Humans
- Zebrafish Proteins/physiology
- Zebrafish
- Animals
- Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor
- Male
- Gene Expression Profiling
- Basic Helix-Loop-Helix Transcription Factors/physiology
- Animals, Genetically Modified
- Proto-Oncogene Proteins c-bcl-2/physiology*
- Radiation Tolerance
- Neoplasm Proteins/biosynthesis
- Neoplasm Proteins/genetics
- Neoplasm Proteins/physiology
- Time Factors
- Mosaicism
- Genes, bcl-2
- Cell Transformation, Neoplastic/genetics*
- Gene Expression Regulation, Leukemic
- PubMed
- 17252014 Full text @ Leukemia
Citation
Chen, J., Jette, C., Kanki, J.P., Aster, J.C., Look, A.T., and Griffin, J.D. (2007) NOTCH1-induced T-cell leukemia in transgenic zebrafish. Leukemia. 21(3):462-471.
Abstract
Activating mutations in the NOTCH1 gene have been found in about 60% of patients with T-cell acute lymphoblastic leukemia (T-ALL). In order to study the molecular mechanisms by which altered Notch signaling induces leukemia, a zebrafish model of human NOTCH1-induced T-cell leukemia was generated. Seven of sixteen mosaic fish developed a T-cell lymphoproliferative disease at about 5 months. These neoplastic cells extensively invaded tissues throughout the fish and caused an aggressive and lethal leukemia when transplanted into irradiated recipient fish. However, stable transgenic fish exhibited a longer latency for leukemia onset. When the stable transgenic line was crossed with another line overexpressing the zebrafish bcl2 gene, the leukemia onset was dramatically accelerated, indicating synergy between the Notch pathway and the bcl2-mediated antiapoptotic pathway. Reverse transcription-polymerase chain reaction analysis showed that Notch target genes such as her6 and her9 were highly expressed in NOTCH1-induced leukemias. The ability of this model to detect a strong interaction between NOTCH1 and bcl2 suggests that genetic modifier screens have a high likelihood of revealing other genes that can cooperate with NOTCH1 to induce T-ALL.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping