Open AccessTEL-AML1 transgenic zebrafish model of precursor B cell acute lymphoblastic leukemia
Author(s) -
Hatem E. Sabaawy,
Akira Mizuki,
Lisa J. Embree,
HuaiJen Tsai,
Matthew F. Starost,
Dennis D. Hickstein
Publication year - 2006
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0603349103
Subject(s) - zebrafish , biology , leukemia , clone (java method) , cancer research , lymphoid leukemia , progenitor cell , somatic evolution in cancer , transgene , mutation , microbiology and biotechnology , genetics , stem cell , gene
Acute lymphoblastic leukemia (ALL) is a clonal disease that evolves through the accrual of genetic rearrangements and/or mutations within the dominant clone. TheTEL-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 ofTEL-AML1 -induced leukemia have not been identified. To study the origin ofTEL-AML1 -induced ALL, we generated transgenic zebrafish expressingTEL-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 thatTEL-AML1 induces a B cell differentiation arrest, and that leukemia development is associated with loss ofTEL expression and elevatedBcl2 /Bax ratio. TheTEL-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.