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TEL-AML1 transgenic zebrafish model of precursor B cell acute lymphoblastic leukemia
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| Zeitschriftentitel: | Proceedings of the National Academy of Sciences |
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| Personen und Körperschaften: | , , , , , |
| In: | Proceedings of the National Academy of Sciences, 103, 2006, 41, S. 15166-15171 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Proceedings of the National Academy of Sciences
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| Schlagwörter: |
| Zusammenfassung: | <jats:p> Acute lymphoblastic leukemia (ALL) is a clonal disease that evolves through the accrual of genetic rearrangements and/or mutations within the dominant clone. The <jats:italic>TEL-AML1</jats:italic> ( <jats:italic>ETV6-RUNX1</jats:italic> ) fusion in precursor-B (pre-B) ALL is the most common genetic rearrangement in childhood cancer; however, the cellular origin and the molecular pathogenesis of <jats:italic>TEL-AML1</jats:italic> -induced leukemia have not been identified. To study the origin of <jats:italic>TEL-AML1</jats:italic> -induced ALL, we generated transgenic zebrafish expressing <jats:italic>TEL-AML1</jats:italic> either ubiquitously or in lymphoid progenitors. <jats:italic>TEL-AML1</jats:italic> expression in all lineages, but not lymphoid-restricted expression, led to progenitor cell expansion that evolved into oligoclonal B-lineage ALL in 3% of the transgenic zebrafish. This leukemia was transplantable to conditioned wild-type recipients. We demonstrate that <jats:italic>TEL-AML1</jats:italic> induces a B cell differentiation arrest, and that leukemia development is associated with loss of <jats:italic>TEL</jats:italic> expression and elevated <jats:italic>Bcl2</jats:italic> / <jats:italic>Bax</jats:italic> ratio. The <jats:italic>TEL-AML1</jats:italic> transgenic zebrafish models human pre-B ALL, identifies the molecular pathways associated with leukemia development, and serves as the foundation for subsequent genetic screens to identify modifiers and leukemia therapeutic targets. </jats:p> |
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| Umfang: | 15166-15171 |
| ISSN: |
1091-6490
0027-8424 |
| DOI: | 10.1073/pnas.0603349103 |