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

Hatem Sabaawy, Mizuki Azuma, Lisa J. Embree, Huai Jen Tsai, Matthew F. Starost, Dennis D. Hickstein

Research output: Contribution to journalArticlepeer-review

135 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)15166-15171
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number41
DOIs
StatePublished - Oct 10 2006

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Childhood cancer
  • Genetics
  • Stem cell
  • Translocation

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