NOTCH1-induced T-cell leukemia in transgenic zebrafish

Leukemia. 2007 Mar;21(3):462-71. doi: 10.1038/sj.leu.2404546. Epub 2007 Jan 25.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Apoptosis
  • Basic Helix-Loop-Helix Transcription Factors / physiology
  • Cell Transformation, Neoplastic / genetics*
  • Female
  • Gamma Rays
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic
  • Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor
  • Genes, bcl-2
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell / etiology*
  • Leukemia-Lymphoma, Adult T-Cell / genetics
  • Male
  • Mosaicism
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology
  • Neoplasm Transplantation
  • Oncogenes
  • Proto-Oncogene Proteins c-bcl-2 / physiology*
  • Radiation Chimera
  • Radiation Tolerance
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / physiology*
  • Recombinant Fusion Proteins / physiology
  • Signal Transduction
  • Time Factors
  • Zebrafish
  • Zebrafish Proteins / physiology


  • Basic Helix-Loop-Helix Transcription Factors
  • Her6 protein, zebrafish
  • NOTCH1 protein, human
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptor, Notch1
  • Recombinant Fusion Proteins
  • Zebrafish Proteins
  • her9 protein, zebrafish