ZFIN ID: ZDB-PUB-090616-53
Heritable T-cell malignancy models established in a zebrafish phenotypic screen
Frazer, J.K., Meeker, N.D., Rudner, L., Bradley, D.F., Smith, A.C., Demarest, B., Joshi, D., Locke, E.E., Hutchinson, S.A., Tripp, S., Perkins, S.L., and Trede, N.S.
Date: 2009
Source: Leukemia   23(10): 1825-1835 (Journal)
Registered Authors: Demarest, Bradley, Frazer, Kimble, Hutchinson, Sarah, Trede, Nick
Keywords: lymphoma, zebrafish, T lymphocyte, genetic screen
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal*
  • Flow Cytometry
  • Genetic Predisposition to Disease*
  • Green Fluorescent Proteins/genetics
  • Green Fluorescent Proteins/metabolism
  • Humans
  • Immunoenzyme Techniques
  • Incidence
  • Mutagenesis
  • Phenotype
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transgenes/genetics*
  • Zebrafish/genetics*
PubMed: 19516274 Full text @ Leukemia
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.