Abstract

EXCEED THE SPACE PROVIDED. Runxl-CBFI_ is a heterodimeric transcription factor required for the emergence of hematopoietic stem cells in the embryo. During postnatal life mutations in the RUNXl and CBFB genes in a hematopoietic stem cell or committed progenitor contributes to the formation of human leukemias. The RUNX1 (AML1) gene is disrupted by about a dozen different chromosomal translocations, including the t(8;21 ), t(12;21), and t(3;21) in acute myeloid and pediatric lymphoblastic leukemias, and in therapy related leukemias and myelodysplasias, respectively. The CBFB gene is rearranged in acute myeloid leukemias by the inv(16). Together, the RUNX1 and CBFB genes are rearranged in approximately one quarter of all acute myeloid and lymphoblastic leukemias. Here we propose to examine the requirement for the Runxl-CBFI_ heterodimer throughout normal hematopoietic development in mice. We will determine whether Runxl-CBF_ function in a specialized 'hemogenic endothelium' is necessary and sufficient in order to produce the first hematopoietic stem cells. We will begin to identify the signals that specify the first hematopoietic stem cells by characterizing the cis- acting sequences that regulate Runxl expression in the embryo. Finally we will examine the requirement for continued Runxl-CBFI_ function during later stages of postnatal hematopoiesis. PERFORMANCE SITE ========================================Section End===========================================

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA058343-12
Application #
6829155
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Cole, John S
Project Start
1993-08-10
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
12
Fiscal Year
2005
Total Cost
$403,055
Indirect Cost

  Institution

Name
Dartmouth College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755

  Publications

Yzaguirre, Amanda D; de Bruijn, Marella F T R; Speck, Nancy A (2017) The Role of Runx1 in Embryonic Blood Cell Formation. Adv Exp Med Biol 962:47-64
Yzaguirre, Amanda D; Speck, Nancy A (2016) Insights into blood cell formation from hemogenic endothelium in lesser-known anatomic sites. Dev Dyn 245:1011-28
Yzaguirre, Amanda D; Speck, Nancy A (2016) Extravascular endothelial and hematopoietic islands form through multiple pathways in midgestation mouse embryos. Dev Biol 415:111-121
Ditadi, Andrea; Sturgeon, Christopher M; Tober, Joanna et al. (2015) Human definitive haemogenic endothelium and arterial vascular endothelium represent distinct lineages. Nat Cell Biol 17:580-91
Imanirad, Parisa; Solaimani Kartalaei, Parham; Crisan, Mihaela et al. (2014) HIF1? is a regulator of hematopoietic progenitor and stem cell development in hypoxic sites of the mouse embryo. Stem Cell Res 12:24-35
de Pater, Emma; Kaimakis, Polynikis; Vink, Chris S et al. (2013) Gata2 is required for HSC generation and survival. J Exp Med 210:2843-50
Clarke, Raedun L; Yzaguirre, Amanda D; Yashiro-Ohtani, Yumi et al. (2013) The expression of Sox17 identifies and regulates haemogenic endothelium. Nat Cell Biol 15:502-10
Guo, Hong; Ma, Ou; Speck, Nancy A et al. (2012) Runx1 deletion or dominant inhibition reduces Cebpa transcription via conserved promoter and distal enhancer sites to favor monopoiesis over granulopoiesis. Blood 119:4408-18
Yokomizo, Tomomasa; Yamada-Inagawa, Tomoko; Yzaguirre, Amanda D et al. (2012) Whole-mount three-dimensional imaging of internally localized immunostained cells within mouse embryos. Nat Protoc 7:421-31
Pajcini, K V; Speck, N A; Pear, W S (2011) Notch signaling in mammalian hematopoietic stem cells. Leukemia 25:1525-32

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