1. ¹Department of Pediatrics, University of Utah, Salt Lake City, UT, USA
2. ²Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
3. ³Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
4. ⁴ARUP Institute, Salt Lake City, UT, USA
5. ⁵Department of Pathology, University of Utah, Salt Lake City, UT, USA

Correspondence: Dr JK Frazer, Huntsman Cancer Institute, HCI-4264, 2000 Circle of Hope, Salt Lake City, UT 84112, USA. E-mail: kimble.frazer@hsc.utah.edu; Dr N Trede, E-mail: nikolaus.trede@hci.utah.edu

⁶These authors contributed equally to this work.

Received 12 February 2009; Revised 21 April 2009; Accepted 23 April 2009; Published online 11 June 2009.

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.