Research indicates that epigenetic alteration of gene regulation allows survival of premalignant cells and that diet influences epigenetic regulation. By understanding dietary factors that influence epigenetic regulation of gene expression, we may be able to design effective cancer preventive strategies. This exploratory study will investigate the hypothesis that manipulation of omega 3/omega 6 fatty acid ratios can affect WNT pathway signaling through epigenetic regulation of SFRP levels in myeloid leukemias. Two experimental models will be used. To assay the connection between cancer progression, omega fatty acids, and SFRP methylation a mouse BCR-ABL chronic myelogenous leukemia (CML) blast crisis model will be used. In the first Specific Aim, we will determine the effect of high omega 3 canola oil vs. low omega 3 corn oil on the incidence of blast crisis CML. This will be correlated with the promoter methylation status of five SFRP genes using methylation specific PCR. The activity of the WNT pathway will also be determined in this animal model through flow cytometry and confocal microscopy.
In Specific Aim 2, a second in vitro model of hematopoietic stem cell differentiation will be used for more manipulative studies of the effect of omega 3/ omega 6 fatty acids on differentiation and DNA methylation. The EML-clone1 cell differentiation system will be used to characterize the effect of ratios of omega 3 and omega 6 fatty acids on myeloid cell differentiation into the macrophage and granulocyte lineages. Immunophenotyping with flow cytometry will be employed to follow cellular differentiation. The studies in this proposal will test our central hypothesis in both in vivo and in vitro systems and provide preliminary evidence for preventive therapeutic approaches using dietary fatty acids. PROJECT
It has become increasingly apparent that dietary factors can affect our risk to diseases such as cancer. This proposal will draw connections between exposure to specific types of fatty acids, such as those present in fish oils, to protection from cancer. A mechanism has been proposed for the basis of this interaction and will be tested.
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| Varney, Melinda E; Buchanan, James T; Dementieva, Yulia et al. (2011) A high omega-3 fatty acid diet has different effects on early and late stage myeloid progenitors. Lipids 46:47-57 |
| Fan, Jun; Eastham, Linda; Varney, Melinda E et al. (2010) Silencing and re-expression of retinoic acid receptor beta2 in human melanoma. Pigment Cell Melanoma Res 23:419-29 |
| Napper, Jennifer M; Sollars, Vincent E (2010) 17-N-Allylamino-17-demethoxygeldanamycin induces a diverse response in human acute myelogenous cells. Leuk Res 34:1493-500 |
| Varney, Melinda E; Hardman, W Elaine; Sollars, Vincent E (2009) Omega 3 fatty acids reduce myeloid progenitor cell frequency in the bone marrow of mice and promote progenitor cell differentiation. Lipids Health Dis 8:9 |
