The zebrafish is the vertebrate animal model of choice for studies of embryogenesis due to its rapid ex vivo development of transparent embryos. Genetic and embryological studies indicate that the regulation of embryogenesis is highly conserved between zebrafish and mammals. Specifically, virtually all the important regulators of hematopoiesis have homologs in the zebrafish that perform similar functions. My lab has been using zebrafish to study the genetic control of hematopoiesis. We are especially interested in the roles of RUNX1 and CBFB, two genes frequently affected in human leukemias. Previously we developed a zebrafish line with a truncation mutation (W84X) in the runx1 gene. Characterization of this line showed that fetal (or larval in zebrafish) and adult hematopoiesis share a common stem cell pool, but runx1 is only required for the initiation of larval hematopoiesis. Now we have developed several cbfb mutant lines through a novel technology called zinc finger nuclease. Preliminary characterization of these lines revealed that cbfb is required for the proper development of definitive hematopoiesis. We will continue our analysis of these cbfb mutant lines for a better understanding of cbfb function in hematopoiesis, as well as other developmental processes. We have also generated zebrafish lines carrying transgene CBFB-MYH11, which is found in many human leukemia cases. The CBFB-MYH11 transgene is under an inducible control mechanism for its expression, so we can express the transgene at any time point during development. We hope to use these lines to characterize the function of this important leukemia gene. Another major effort in the lab is to use the zebrafish as an in vivo model to validate and confirm the biological effects of small molecules, which are being generated through our other project for the development of novel anti-leukemia drugs. The zebrafish also serve the function of toxicity studies for these chemicals. Our experience so far has demonstrated that the zebrafish is a sensitive and extremely fast in vivo system for these purposes.

Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2011
Total Cost
$467,824
Indirect Cost
Name
National Human Genome Research Institute
Department
Type
DUNS #
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Morita, Ken; Suzuki, Kensho; Maeda, Shintaro et al. (2017) Genetic regulation of the RUNX transcription factor family has antitumor effects. J Clin Invest 127:2815-2828
Kwon, Erika M; Connelly, John P; Hansen, Nancy F et al. (2017) iPSCs and fibroblast subclones from the same fibroblast population contain comparable levels of sequence variations. Proc Natl Acad Sci U S A 114:1964-1969
Sood, Raman; Kamikubo, Yasuhiko; Liu, Paul (2017) Role of RUNX1 in hematological malignancies. Blood 129:2070-2082
Gore, Aniket V; Athans, Brett; Iben, James R et al. (2016) Epigenetic regulation of hematopoiesis by DNA methylation. Elife 5:e11813
Li, H; Zhao, X; Yan, X et al. (2016) Runx1 contributes to neurofibromatosis type 1 neurofibroma formation. Oncogene 35:1468-74
Hyde, R K; Zhao, L; Alemu, L et al. (2015) Runx1 is required for hematopoietic defects and leukemogenesis in Cbfb-MYH11 knock-in mice. Leukemia 29:1771-8
Hao, Hong; Veleri, Shobi; Sun, Bo et al. (2014) Regulation of a novel isoform of Receptor Expression Enhancing Protein REEP6 in rod photoreceptors by bZIP transcription factor NRL. Hum Mol Genet 23:4260-71
Connelly, Jon P; Kwon, Erika M; Gao, Yongxing et al. (2014) Targeted correction of RUNX1 mutation in FPD patient-specific induced pluripotent stem cells rescues megakaryopoietic defects. Blood 124:1926-30
Bresciani, Erica; Carrington, Blake; Wincovitch, Stephen et al. (2014) CBF? and RUNX1 are required at 2 different steps during the development of hematopoietic stem cells in zebrafish. Blood 124:70-8
Sood, Raman; Carrington, Blake; Bishop, Kevin et al. (2013) Efficient methods for targeted mutagenesis in zebrafish using zinc-finger nucleases: data from targeting of nine genes using CompoZr or CoDA ZFNs. PLoS One 8:e57239

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