Heritable T-cell malignancy models established in a zebrafish phenotypic screen
Open Access
- 11 June 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Leukemia
- Vol. 23 (10), 1825-1835
- https://doi.org/10.1038/leu.2009.116
Abstract
T-cell neoplasias are common in pediatric oncology, and include acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LBL). These cancers have worse prognoses than their B-cell counterparts, and their treatments carry significant morbidity. Although many pediatric malignancies have characteristic translocations, most T-lymphocyte-derived diseases lack cytogenetic hallmarks. Lacking these informative lesions, insight into their molecular pathogenesis is less complete. Although dysregulation of the NOTCH1 pathway occurs in a substantial fraction of cases, many other genetic lesions of T-cell malignancy have not yet been determined. To address this deficiency, we pioneered a phenotype-driven forward-genetic screen in zebrafish (Danio rerio). Using transgenic fish with T-lymphocyte-specific expression of enhanced green fluorescent protein (EGFP), we performed chemical mutagenesis, screened animals for GFP+ tumors, and identified multiple lines with a heritable predisposition to T-cell malignancy. In each line, the patterns of infiltration and morphological appearance resembled human T-ALL and T-LBL. T-cell receptor analyses confirmed their clonality. Malignancies were transplantable and contained leukemia-initiating cells, like their human correlates. In summary, we have identified multiple zebrafish mutants that recapitulate human T-cell neoplasia and show heritable transmission. These vertebrate models provide new genetic platforms for the study of these important human cancers.Keywords
This publication has 46 references indexed in Scilit:
- Immunology and zebrafish: Spawning new models of human diseaseDevelopmental & Comparative Immunology, 2008
- Zebrafish mutants with disrupted early T‐cell and thymus development identified in early pressure screenDevelopmental Dynamics, 2008
- Co-injection strategies to modify radiation sensitivity and tumor initiation in transgenic ZebrafishOncogene, 2008
- Definitive hematopoiesis initiates through a committed erythromyeloid progenitor in the zebrafish embryoDevelopment, 2007
- Familial T-cell non-Hodgkin lymphoma caused by biallelic MSH2 mutationsJournal of Medical Genetics, 2007
- NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growthProceedings of the National Academy of Sciences of the United States of America, 2006
- TEL-AML1 transgenic zebrafish model of precursor B cell acute lymphoblastic leukemiaProceedings of the National Academy of Sciences of the United States of America, 2006
- Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic LeukemiaScience, 2004
- Systematic Population-Based Assessment of Cancer Risk in First-Degree Relatives of Cancer ProbandsJNCI Journal of the National Cancer Institute, 1994
- Familial Leukaemia: A Study of 909 FamiliesScandinavian Journal of Haematology, 1975