Project Funding Details

Background: Folate is a B vitamin that is an important factor for a number of metabolic pathways. While dietary folate deficiency is a problem in much of the world, in the U.S. and Canada mandatory folate supplementation of enriched grain products has largely eliminated dietary folate deficiency in these countries. Folate levels have been linked to increased cancer risk in a puzzling way: dietary folate deficiency has been associated with increased risk of some cancers, while excessive folate supplementation may also be associated with increased cancer risks. Importantly, we know almost nothing about how inadequate or excessive folate uptake could influence cancer initiation. Our preliminary data indicate that both low folate and high folate diets result in stable reductions in hematopoietic progenitor cell fitness, coincident with strikingly similar impairment of metabolism. We have also shown that low folate diets promote leukemogenesis initiated by Bcr-Abl, the translocation product that initiates chronic myelogenous leukemias. Objectives: We hypothesize that both low folate and high folate diets result in impaired metabolism by reducing the activities of key biosynthetic enzymes, contributing to stable reductions of hematopoietic progenitor cell fitness, leading to alterations in the adaptive landscape and increased leukemogenesis. We further propose that oncogenes like Bcr-Abl become adaptive in progenitor pools exposed to either insufficient or excess folate in part by boosting glycolysis, which partially compensates for metabolic and anabolic deficiencies caused by folate imbalance. We will test our hypothesis by exploring how altered folate diets impact metabolism, stem and progenitor cell fitness, and leukemogenesis. To this end, we will ask how low and high folate diets influence the activity of key metabolic enzymes, metabolite levels, hematopoietic progenitor cell fitness, and selection for particular oncogenic events. Setting & Methods: The University of Colorado Anschutz Medical Campus provides an ideal environment rich in cancer, nutritional and metabolic research. This proposal will focus on mouse models, and will employ various biochemical techniques including enzymatic assays, NMR and mass spectrometry. Potential Impact: With 350 million people in North America at risk for excessive folate intake, and much of the rest of the world potentially deficient in folate, it is imperative that we know more about the role of folate in carcinogenesis. Our proposed studies should complement epidemiological studies of links between dietary folate, metabolism, tissue fitness and cancer in humans, with important public policy implications. Keywords: folate, supplementation, leukemia, fitness, Bcr-Abl

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, and inadequate folate intake has also been associated with increased rates of several cancers. On the other hand, supplementation with folate at levels well above the Recommended Daily Allowance (RDA) has also been associated with increased cancer risk. Still, differences in genetics, lifestyles and diets among people have made it difficult to accurately determine the importance of dietary folate in cancer occurrence. Given mandated folate supplementation of processed grain products and common consumption of supplements, fortified breakfast cereals and other products with added folate, folate intake in the U.S. is often substantially above the RDA. We have made the unexpected observation that white blood cell progenitors from mice fed diets either high or low in folate exhibit a strikingly similar phenotype: similarly impaired metabolism with reduced cell fitness (cells are less able to contribute to blood cell production). We have also shown that a low folate diet substantially increases leukemia development initiated by a particular cancer-causing mutant gene (oncogene), Bcr-Abl. We propose to test a novel hypothesis that represents a substantial departure from current paradigms: that diets either too low or too high in folate impair metabolism by interfering with the activities of key enzymes, leading to reduced fitness of stem cells, which increases the advantage provided to cells by particular oncogenes (these oncogenes are "adaptive"). This enhanced selection for oncogenic mutations in turn increases the risk of cancer. These studies could provide a paradigm-shifting explanation for the paradoxical associations between diets both low and high in folates and cancer predisposition: certain oncogenic mutations that may be non-advantageous within healthy stem cell pools may be adaptive in stem cell pools with impaired fitness due to dietary imbalances. Impact: While most countries do not mandate folate supplementation and folate deficiency remains endemic in much of the underdeveloped world, folate consumption in the U.S. is often well above recommended levels. A better understanding of how dietary folate influences disease predisposition will be essential for guiding public policy decisions. Animal models and mechanistic insight into the importance of dietary folate levels for cancer prevention will be critical for decisions on whether and how much to supplement. While the proposed studies are in mice, which allows for tight control over diet, our proposed experimental plan should complement and even guide clinical and epidemiological studies of links between dietary folate, tissue fitness, and cancer in humans. Keywords: folate, supplementation, leukemia, fitness