TEL-AML1 transgenic zebrafish model of precursor B cell acute lymphoblastic leukemia.
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.
Sabaawy
Hatem E
HE
Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. sabaawyh@mail.nih.gov
Azuma
Mizuki
M
Embree
Lisa J
LJ
Tsai
Huai-Jen
HJ
Starost
Matthew F
MF
Hickstein
Dennis D
DD
D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000235:genetics; D002648:Child; D050676:Core Binding Factor Alpha 2 Subunit / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D020868:Gene Silencing; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D015854:Up-Regulation / Q000235:genetics; D015027:Zebrafish / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein