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

doi:10.1073/pnas.0603349103

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

CINJ - Basic Research

Research output: Contribution to journal › Article › peer-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 language	English (US)
Pages (from-to)	15166-15171
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	103
Issue number	41
DOIs	https://doi.org/10.1073/pnas.0603349103
State	Published - Oct 10 2006

All Science Journal Classification (ASJC) codes

General

Keywords

Childhood cancer
Genetics
Stem cell
Translocation

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title = "TEL-AML1 transgenic zebrafish model of precursor B cell lymphoblastic leukemia",

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.",

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TEL-AML1 transgenic zebrafish model of precursor B cell lymphoblastic leukemia. / Sabaawy, Hatem; Azuma, Mizuki; Embree, Lisa J.; Tsai, Huai Jen; Starost, Matthew F.; Hickstein, Dennis D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 41, 10.10.2006, p. 15166-15171.

Research output: Contribution to journal › Article › peer-review

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