Heritable T-cell malignancy models established in a zebrafish phenotypic screen.
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.
Frazer
J K
JK
Department of Pediatrics, University of Utah, Salt Lake City, UT, USA. kimble.frazer@hsc.utah.edu
Meeker
N D
ND
Rudner
L
L
Bradley
D F
DF
Smith
A C H
AC
Demarest
B
B
Joshi
D
D
Locke
E E
EE
Hutchinson
S A
SA
Tripp
S
S
Perkins
S L
SL
Trede
N S
NS
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*
D012333:RNA, Messenger; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins