NOTCH1-induced T-cell leukemia in transgenic zebrafish

• Published in: Leukemia Vol. 21; no. 3; pp. 462 - 471
• Main Authors: CHEN, J, JETTE, C, KANKI, J. P, ASTER, J. C, LOOK, A. T, GRIFFIN, J. D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01.03.2007; Nature Publishing Group
• Subjects: Acute lymphoblastic leukemia; Animal tissues; Animals; Animals, Genetically Modified; Apoptosis; Basic Helix-Loop-Helix Transcription Factors - physiology; Biological and medical sciences; Cancer; Cell Transformation, Neoplastic - genetics; Control; Danio rerio; Female; Freshwater; Gamma Rays; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; Genes; Genes, bcl-2; Genetic aspects; Genetic screening; Hematologic and hematopoietic diseases; Humans; Immunoproliferative diseases; Latency; Leukemia; Leukemia-Lymphoma, Adult T-Cell - etiology; Leukemia-Lymphoma, Adult T-Cell - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphatic leukemia; Lymphocytes; Lymphocytes T; Lymphocytic leukemia; Male; Medical sciences; Molecular modelling; Mosaicism; Mutation; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Neoplasm Transplantation; Notch1 protein; Oncogenes; Oncology; Pathogenesis; Pediatrics; Polymerase chain reaction; Proto-Oncogene Proteins c-bcl-2 - physiology; Radiation Chimera; Radiation Tolerance; Receptor, Notch1 - genetics; Receptor, Notch1 - physiology; Recombinant Fusion Proteins - physiology; Reverse transcription; Risk factors; Signal Transduction; Strong interactions (field theory); Time Factors; Transgenic fish; Tumorigenesis; Zebra fish; Zebrafish; Zebrafish Proteins - physiology; United States; United States > US; Notch receptor; Hematology; Notch; Malignant hemopathy; bc12; Vertebrata; Brachydanio rerio; Precusor T lymphoblastic leukemia; Pisces; T-Lymphocyte; Acute lymphocytic leukemia; zebrafish; T-ALL
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2404546

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.