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Curative strategies for chronic myelogenous leukemia

Vincent E. Sollars, Ph.D.

Eml Cells Macrophages Pseudomonas
EML cells – Shown here is our model system for the in vitro study of fatty acid effects on hematopoiesis. These EML cells are a murine hematopoietic stem cell line. The cells here are EML cells differentiated into macrophages. Macrophages and Pseudomonas - Epifluorescent images of naïve macrophages produced from bone marrow progenitor cells harvested from mice after a 20 minute exposure to P. aeruginosa. The nuclei are stained red with ethidium bromide, while the endoplasmic reticulum is stained blue with ER-Tracker™ Blue-White DPX and the bacteria appear green due to GFP expression.

Curative strategies for chronic myelogenous leukemia (CML) blast crisis are inadequate. The progression of this disease to blast crisis is caused by blockage of differentiation in myeloid progenitor cells. Our preliminary data in mice show that omega-3 fatty acids can reduce myeloid progenitor cell levels and induce differentiation of these cells in vivo. We propose that dietary intake of omega-3 fatty acids can be used as a preventive strategy for blast crisis progression in CML. We hypothesize that omega-3 fatty acids can increase differentiation of bone marrow progenitor cells through epigenetic mechanisms and that this effect may be applicable to slowing progression of CML to blast crisis. We will investigate the effects on omega-3 fatty acids on myeloid differentiation using the EML cell culture model to ascertain if FA manipulation can influence the rate of hematopoietic differentiation in an in vitro model. We will further investigate omega-3 fatty acid activity by determining the effects of n-3/n-6 fatty acid ratios on hematopoietic differentiation in vivo in C57Bl/6 mice. Finally, we will use a BCR-ABL transgenic mouse model to determine if n-3/n-6 fatty acid levels affect blast crisis progression. Experimental methods will include colony forming cell assays to determine progenitor cell frequencies, flow cytometry for immunophenotyping, and histological analysis of tissues. Cellular differentiation and epigenetic gene regulation are intimately connected. Many nutritional factors that inhibit cancers have been associated with epigenetic changes, such as post-translational histone modifications and DNA methylation. We will determine if epigenetic effects are being induced by omega-3 fatty acid exposure by examining changes in cellular memory. Successful accomplishment of our aims will advance our understanding of the biological effects of these FAs and determine the possibility of omega-3 fatty acid augmentation of diet as a preventive strategy for progression of CML to blast crisis.



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