The purpose of this continuing project is to better understand the roles of altered hematopoietic stem or progenitor cell (HPC) differentiation and cytogenetic damage in early events in the development of acute myelogenous leukemia (sAML) following treatment with alkylating chemotherapeutic agents or benzene. Consistent with emerging models of carcinogenesis, sAML is an evolutionary process involving selection of clonal cytogenetic events in HPC together with microenvironmental changes in stromal cells that ultimately contribute to the development of myelodysplasia (MDS) and sAML. During the previous funding period a multistep model for the evolution of sAML was developed in which drug- induced alterations in HPC proliferation lead to development of a distinct pattern of clonal cytogenetic abnormalities (C.A.) and progressive dysplastic changes that select for the emergence of the malignant cell phenotype. Using this model as a hypothesis, the pattern of expression of genes known to be involved in regulation of normal hematopoiesis will be compared between normal human bone marrow (BM) cells and BM treated with alkylating agents in vitro. Treatment related changes in transcriptional regulation of gene expression occurring in purified sub-populations of human CD34+ BM cells in liquid culture will be assessed using a variety of molecular biology techniques and correlated with flow cytometric analysis of cell phenotype, clonogenic function in HPC, and cytokine production in stromal cells. Fluorescence in situ hybridization also will be used to evaluate the potential of individual agents to produce C.A. in specific sub-populations of CD34+ human BM cells. Finally, patterns of gene expression will be correlated with genotype, phenotype and functional clonogenic response in BM cells obtained from patients with MDS or evolving sAML.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-ALTX-4 (01))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Schools of Pharmacy
United States
Zip Code
Irons, Richard D; Le, Anh Tuan (2008) Dithiocarbamates and viral IL-10 collaborate in the immortalization and evasion of immune response in EBV-infected human B lymphocytes. Chem Biol Interact 172:81-92
Gross, S A; Zheng, J H; Le, A T et al. (2006) PU.1 phosphorylation correlates with hydroquinone-induced alterations in myeloid differentiation and cytokine-dependent clonogenic response in human CD34(+) hematopoietic progenitor cells. Cell Biol Toxicol 22:229-41
Zheng, J H; Pyatt, D W; Gross, S A et al. (2004) Hydroquinone modulates the GM-CSF signaling pathway in TF-1 cells. Leukemia 18:1296-304
Kerzic, Patrick J; Pyatt, David W; Zheng, Jia Hua et al. (2003) Inhibition of NF-kappaB by hydroquinone sensitizes human bone marrow progenitor cells to TNF-alpha-induced apoptosis. Toxicology 187:127-37
Irons, R D; Pyatt, D W; Gross, S A et al. (2001) Hematopoietic stem and progenitor cells as targets for biological reactive intermediates. Adv Exp Med Biol 500:441-9
Baker, R K; Kurz, E U; Pyatt, D W et al. (2001) Benzene metabolites antagonize etoposide-stabilized cleavable complexes of DNA topoisomerase IIalpha. Blood 98:830-3
Irons, R D; Stillman, W S; Pyatt, D W et al. (2001) Comparative toxicity of dithiocarbamates and butadiene metabolites in human lymphoid and bone marrow cells. Chem Biol Interact 135-136:615-25
Stillman, W S; Varella-Garcia, M; Irons, R D (2000) The benzene metabolite, hydroquinone, selectively induces 5q31- and -7 in human CD34+CD19- bone marrow cells. Exp Hematol 28:169-76
Pyatt, D W; Yang, Y; Stillman, W S et al. (2000) Hydroquinone inhibits PMA-induced activation of NFkappaB in primary human CD19+ B lymphocytes. Cell Biol Toxicol 16:41-51
Pyatt, D W; Yang, Y; Mehos, B et al. (2000) Hematotoxicity of the chinese herbal medicine Tripterygium wilfordii hook f in CD34-positive human bone marrow cells. Mol Pharmacol 57:512-8

Showing the most recent 10 out of 24 publications