The basic thesis of this proposal is that Hox homeobox genes are important regulators of normal hematopoiesis. This application will test two hypotheses; 1) that blood cell differentiation is regulated by the orchestrated deployment of specific Hox genes; 2) that Hox proteins regulate gene transcription by binding DNA as heterodimers with other partners including Pbx; and 3) that retinoids and their receptors are key regulators of Hox expression. In order to test these hypotheses, Dr. Lawrence proposes four specific objectives. The first specific aim will further characterize hematologic defects in HoxA9 null mice. This will include transplant studies to delineate stem cell defects; a survey of adhesion molecule expression and a study of the effects of other homeobox mutations on the HoxA9 null phenotype. The second specific aim will attempt to identify direct target genes for Hox genes in blood cells. A Tet-inducible system will be used to express HoxA9 in a novel HoxA9 null cell line using a cDNA array to analyze differential gene expression. The third specific aim will characterize the hematopoietic consequences of compound homeobox gene mutations. The consequences of mutants involving members of the same Hox paralog or members of the same cluster will be analyzed. The fourth specific aim will characterize the role of retinoids and their receptors as regulators of Hox genes in blood cells. This will involve a) analysis of Hox gene activation in hematopoietic precursors by retinoic acid and b) assessing responses of specific Hox deficient blood cells to retinoids.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK048642-05
Application #
6196975
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Badman, David G
Project Start
1996-06-01
Project End
2004-08-31
Budget Start
2000-09-15
Budget End
2001-08-31
Support Year
5
Fiscal Year
2000
Total Cost
$245,655
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Hu, Yu-Long; Passegue, Emmanuelle; Fong, Stephen et al. (2007) Evidence that the Pim1 kinase gene is a direct target of HOXA9. Blood 109:4732-8
Bijl, Janet; Thompson, Alexander; Ramirez-Solis, Ramiro et al. (2006) Analysis of HSC activity and compensatory Hox gene expression profile in Hoxb cluster mutant fetal liver cells. Blood 108:116-22
Ferrell, Christina M; Dorsam, Sheri T; Ohta, Hideaki et al. (2005) Activation of stem-cell specific genes by HOXA9 and HOXA10 homeodomain proteins in CD34+ human cord blood cells. Stem Cells 23:644-55
Lawrence, H Jeffrey; Christensen, Julie; Fong, Stephen et al. (2005) Loss of expression of the Hoxa-9 homeobox gene impairs the proliferation and repopulating ability of hematopoietic stem cells. Blood 106:3988-94
Fischbach, Neal A; Rozenfeld, Sofia; Shen, Weifang et al. (2005) HOXB6 overexpression in murine bone marrow immortalizes a myelomonocytic precursor in vitro and causes hematopoietic stem cell expansion and acute myeloid leukemia in vivo. Blood 105:1456-66
Pineault, Nicolas; Abramovich, Carolina; Ohta, Hideaki et al. (2004) Differential and common leukemogenic potentials of multiple NUP98-Hox fusion proteins alone or with Meis1. Mol Cell Biol 24:1907-17
Dorsam, Sheri Tinnell; Ferrell, Christina M; Dorsam, Glenn P et al. (2004) The transcriptome of the leukemogenic homeoprotein HOXA9 in human hematopoietic cells. Blood 103:1676-84
Schneider, T E; Barland, C; Alex, A M et al. (2003) Measuring stem cell frequency in epidermis: a quantitative in vivo functional assay for long-term repopulating cells. Proc Natl Acad Sci U S A 100:11412-7
Pineault, Nicolas; Buske, Christian; Feuring-Buske, Michaela et al. (2003) Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion gene NUP98-HOXD13 in concert with Meis1. Blood 101:4529-38
Buske, Christian; Feuring-Buske, Michaela; Abramovich, Carolina et al. (2002) Deregulated expression of HOXB4 enhances the primitive growth activity of human hematopoietic cells. Blood 100:862-8

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