PUBLICATION

TEL-AML1 transgenic zebrafish model of precursor B cell acute lymphoblastic leukemia

Authors
Sabaawy, H.E., Azuma, M., Embree, L.J., Tsai, H.J., Starost, M.F., and Hickstein, D.D.
ID
ZDB-PUB-061020-15
Date
2006
Source
Proceedings of the National Academy of Sciences of the United States of America   103(41): 15166-15171 (Journal)
Registered Authors
Azuma, Mizuki, Embree, Lisa, Hickstein, Dennis D., Sabaawy, Hatem, Tsai, Huai-Jen
Keywords
stem cell, translocation, childhood cancer, genetics
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Cell Differentiation/genetics
  • Child
  • Core Binding Factor Alpha 2 Subunit/antagonists & inhibitors
  • Core Binding Factor Alpha 2 Subunit/biosynthesis
  • Core Binding Factor Alpha 2 Subunit/genetics*
  • Disease Models, Animal*
  • Gene Silencing
  • Hematopoietic Stem Cells/pathology
  • Humans
  • Oncogene Proteins, Fusion/antagonists & inhibitors
  • Oncogene Proteins, Fusion/biosynthesis
  • Oncogene Proteins, Fusion/genetics*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology
  • Proto-Oncogene Proteins c-bcl-2/biosynthesis
  • Up-Regulation/genetics
  • Zebrafish/genetics*
  • bcl-2-Associated X Protein/biosynthesis
PubMed
17015828 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
Acute lymphoblastic leukemia (ALL) is a clonal disease that evolves through the accrual of genetic rearrangements and/or mutations within the dominant clone. The TEL-AML1 (ETV6-RUNX1) 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 TEL-AML1-induced leukemia have not been identified. To study the origin of TEL-AML1-induced ALL, we generated transgenic zebrafish expressing TEL-AML1 either ubiquitously or in lymphoid progenitors. TEL-AML1 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 TEL-AML1 induces a B cell differentiation arrest, and that leukemia development is associated with loss of TEL expression and elevated Bcl2/Bax ratio. The TEL-AML1 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.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes