|ZFIN ID: ZDB-PUB-061020-15|
TEL-AML1 transgenic zebrafish model of precursor B cell acute lymphoblastic leukemia
Sabaawy, H.E., Azuma, M., Embree, L.J., Tsai, H.J., Starost, M.F., and Hickstein, D.D.
|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|
|PubMed:||17015828 Full text @ Proc. Natl. Acad. Sci. USA|
Sabaawy, H.E., Azuma, M., Embree, L.J., Tsai, H.J., Starost, M.F., and Hickstein, D.D. (2006) TEL-AML1 transgenic zebrafish model of precursor B cell acute lymphoblastic leukemia. Proceedings of the National Academy of Sciences of the United States of America. 103(41):15166-15171.
ABSTRACTAcute 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.