title: Heritable T-cell malignancy models established in a zebrafish phenotypic screen.
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.
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, UT, USA. kimble.frazer@hsc.utah.edu
authors.forename: J K
authors.initials: JK
authors.lastname: Frazer
authors.forename: N D
authors.initials: ND
authors.lastname: Meeker
authors.forename: L
authors.initials: L
authors.lastname: Rudner
authors.forename: D F
authors.initials: DF
authors.lastname: Bradley
authors.forename: A C H
authors.initials: AC
authors.lastname: Smith
authors.forename: B
authors.initials: B
authors.lastname: Demarest
authors.forename: D
authors.initials: D
authors.lastname: Joshi
authors.forename: E E
authors.initials: EE
authors.lastname: Locke
authors.forename: S A
authors.initials: SA
authors.lastname: Hutchinson
authors.forename: S
authors.initials: S
authors.lastname: Tripp
authors.forename: S L
authors.initials: SL
authors.lastname: Perkins
authors.forename: N S
authors.initials: NS
authors.lastname: Trede
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D015994:Incidence; D016296:Mutagenesis; D010641:Phenotype; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins