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Acute Leukemias

NOTCH1-induced T-cell leukemia in transgenic zebrafish

Leukemia volume 21, pages 462–471 (2007)Cite this article

Abstract

Activating mutations in the NOTCH1 gene have been found in about 60% of patients with T-cell acute lymphoblastic leukemia (T-ALL). In order to study the molecular mechanisms by which altered Notch signaling induces leukemia, a zebrafish model of human NOTCH1-induced T-cell leukemia was generated. Seven of sixteen mosaic fish developed a T-cell lymphoproliferative disease at about 5 months. These neoplastic cells extensively invaded tissues throughout the fish and caused an aggressive and lethal leukemia when transplanted into irradiated recipient fish. However, stable transgenic fish exhibited a longer latency for leukemia onset. When the stable transgenic line was crossed with another line overexpressing the zebrafish bcl2 gene, the leukemia onset was dramatically accelerated, indicating synergy between the Notch pathway and the bcl2-mediated antiapoptotic pathway. Reverse transcription-polymerase chain reaction analysis showed that Notch target genes such as her6 and her9 were highly expressed in NOTCH1-induced leukemias. The ability of this model to detect a strong interaction between NOTCH1 and bcl2 suggests that genetic modifier screens have a high likelihood of revealing other genes that can cooperate with NOTCH1 to induce T-ALL.

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Acknowledgements

We thank J Kutok, J Williams, D Skinner and V Nguyen for histology services; G Kourkoulis, J Kilgore, A Hagen and B Baker for excellent fish care; D Zahrieh for Kaplan–Meier survival analysis; A Letai and D Langenau for reagents and discussions. Supported by grants from the National Institute of Health CA-36167 (JDG), CA-68484 (ATL). JC is a fellow of Leukemia and Lymphoma Society. CJ is supported by a National Institute of Health Program Training Grant in Molecular Hematology.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute of Harvard Medical School, Boston, MA, USA

    J Chen & J D Griffin

  2. Department of Pediatric Oncology, Dana-Farber Cancer Institute of Harvard Medical School, Boston, MA, USA

    C Jette, J P Kanki & A T Look

  3. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA

    J C Aster

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  1. J Chen
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  2. C Jette
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  3. J P Kanki
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  4. J C Aster
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Correspondence to J D Griffin.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Chen, J., Jette, C., Kanki, J. et al. NOTCH1-induced T-cell leukemia in transgenic zebrafish. Leukemia 21, 462–471 (2007). https://doi.org/10.1038/sj.leu.2404546

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