Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Diet-Induced Adaptive Leukemogenesis: BCR-Abl dependent upregulation of folate re

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Diets rich in fruits and vegetables, which are excellent sources of folate (a B vitamin), have been shown to decrease the risk of some cancers. Furthermore, inadequate folate intake has been associated with increased rates of several cancers. However, wide differences in genetics, lifestyles and diets among people have made it difficult to determine the importance of adequate dietary folate in cancer prevention. We have shown that a low folate diet substantially increases leukemia development initiated by a particular cancer-causing mutant gene, Bcr-Abl. Bcr-Abl is the cause of common leukemias in people, but links between these leukemias and diet are virtually unexplored. We have shown that Bcr-Abl increases the levels of a protein required for a cell to uptake folate (the "folate receptor"). We propose that higher levels of this folate receptor, together with other aspects of Bcr-Abl function, provide an early pre-leukemic cell with an advantage relative to normal cells in an individual with insufficient folate levels. Thus, just as animals in the wild compete for limiting food sources, we propose that cells in our bodies compete for limiting nutrients like folate. The more limiting the nutrient is, the greater the selective pressure for mutations that either improve competition for this nutrient or reduce dependency on this nutrient. We hypothesize that Bcr-Abl represents such a mutation. Our unique mouse models will enable us and others to fully explore mechanistic connections between dietary folate and leukemia, and should be adaptable to study connections between other nutritional deficiencies and cancer. PUBLIC HEALTH RELEVANCE: Our proposed studies should complement and even guide clinical and epidemiological studies of links between dietary folate and cancer in humans. For example, our results could stimulate related studies of Bcr-Abl+ human leukemias to determine how common folate receptor upregulation is, whether this upregulation is the direct consequence of Bcr-Abl activity, and most importantly, whether insufficient dietary folate intake is indeed a risk factor for these leukemias. The proposed studies may also stimulate studies of other cancers to ask whether folate deficiency might promote the genesis of these cancers in part by selecting for adaptive oncogenic events. Given that most countries do not mandate folate supplementation and that folate deficiency remains endemic in much of the underdeveloped world, animal models and mechanistic insight into the importance of dietary folate for cancer prevention will be critical for decisions on whether and how much to supplement. A better understanding of how dietary folate influences disease predisposition will be critical for guiding public policy decisions. Finally, the proposed studies could provide an unappreciated explanation for links between various nutritional deficiencies and cancer: these deficiencies could select for oncogenic events adaptive to reduced levels of particular nutrients.

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