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.
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Acknowledgements
We thank Eric Konnick and Lauren Shih for superb technical contributions to this work, Dr Kenneth Boucher for expert statistical analysis and ARUP Institute for histology and immunophenotyping. We also thank Drs Stephen Lessnick, John Parant and Joshua Schiffman for critical appraisal of the paper. JKF was supported by NICHD award K08-HD53350; NM was supported by NICHD award K12-HD001410 and an Alex's Lemonade Stand Young Investigator award; JKF and NM were both supported by the Children's Health Research Center at the University of Utah and by Primary Children's Medical Center Foundation Grants; LR was supported by NIDDK award T32-DK007115; SAH was supported by an NIH Cancer Research Training Grant and an American Cancer Society Fellowship award PF-08-105-01-LIB; NST was supported by NIAID award R21-AI079784 and the Huntsman Cancer Foundation; Huntsman Cancer Institute core facilities supported by Grant P30-CA042014 also contributed to this work.
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Frazer, J., Meeker, N., Rudner, L. et al. Heritable T-cell malignancy models established in a zebrafish phenotypic screen. Leukemia 23, 1825–1835 (2009). https://doi.org/10.1038/leu.2009.116
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DOI: https://doi.org/10.1038/leu.2009.116
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