Abstract B38: Identification of metabolic markers of acute myeloid leukemia in MLL-AF9 transgenic mice

Abstract

Abstract Manifestation of the malignant potential of the neoplastic cell requires metabolic transformation to support the bioenergetic, synthetic, and catabolic requirements of malignancy. Metabolic phenotypes have been associated with every type of cancer and have been used as indicators of disease status, prognosis, and response to therapy. However, few studies investigating changes in metabolism associated with acute leukemia have been reported. We used ex vivo magnetic resonance spectroscopy to investigate changes in metabolite levels in the bone marrow, spleen, and/or blood of leukemic MLL-AF9 transgenic (Tg) mice relative to wild-type littermates. These studies identified differences in more than 20 cellular metabolites and metabolic pathways in leukemic tissues. Significant differences in the levels of metabolites related to glucose metabolism and in flux through glucose metabolic pathways (theWarburg effect) were observed in all tissues examined. Decreased levels of glutamine and glutamate suggest increased utilization of glutaminolysis as an alternative carbon source for macromolecular synthesis. Significant changes in the levels of phospholipid precursors and increased levels of lipids and phospholipids were observed in the bone marrow, suggesting increased flux through lipid biosynthetic pathways and/or decreased lipid breakdown. These changes may allow for increased macromolecular and membrane synthesis to support the hyperproliferative phenotype of leukemic blasts. A switch from high levels of GPC and low levels of PCho to low levels of GPC and high levels of PCho, as we observed here, has also been observed in patients with breast (Aboagye and Bhujwalla, 1999, Cancer Res 59:80) or ovarian cancers (Iorio et al., 2005, Cancer Res 65:9369). Thus, changes in lipid metabolism in leukemic MLL-AF9 Tg mice reflect similar changes in patients with leukemias and other tumors and suggest mechanisms by which metabolic changes may contribute to leukemogenesis in a physiologically relevant context. In contrast to the wide-spread changes in lipid metabolism observed in blood and bone marrow, only a small subset of lipid metabolites were significantly different in the spleens of leukemic mice. The vast majority of metabolic differences in leukemic mice were tissue-specific, being restricted to either the bone marrow or spleen with the largest number and broadest spectrum of metabolic changes detected in the spleen. These data indicate that leukemia cell metabolism is critically dependent on cellular environment, underscoring the importance of development of robust animal models for metabolic studies, as we have described here. Many of the metabolic changes observed in tissues are also reflected in the blood, which may allow for ex vivo assessment of these markers using samples that can be routinely obtained with minimal discomfort to patients. Because this is the first comprehensive study of the “metabolomic” profile associated with leukemia, several markers that have not been previously associated with leukemogenesis and/or that have not been previously associated with any tumor type were identified in this study, revealing novel insights into leukemia cell biology and leukemogenesis. These studies also identify metabolic changes that may be clinically relevant for prognostication, as indicators of therapeutic efficacy, and/or as novel therapeutic targets. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B38.