Rapid Diagnosis and Prognosis of de novo Acute Myeloid Leukemia by Serum Metabonomic Analysis

Abstract

Acute myeloid leukemia (AML) is a life-threatening hematological disease. Novel diagnostic and prognostic markers will be essential for new therapeutics and for significantly improving the disease prognosis. To characterize the metabolic features associated with AML and search for potential diagnostic and prognostic methods, here we analyzed the phenotypic characteristics of serum metabolite composition (metabonome) in a cohort of 183 patients with de novo acute myeloid leukemia together with 232 age- and gender-matched healthy controls using (1)H NMR spectroscopy in conjunction with multivariate data analysis. We observed significant serum metabonomic differences between AML patients and healthy controls and between AML patients with favorable and intermediate cytogenetic risks. Such differences were highlighted by systems differentiations in multiple metabolic pathways including glycolysis/gluconeogenesis, TCA cycle, biosynthesis of proteins and lipoproteins, and metabolism of fatty acids and cell membrane components, especially choline and its phosphorylated derivatives. This demonstrated the NMR-based metabonomics as a rapid and less invasive method for potential AML diagnosis and prognosis. The serum metabolic phenotypes observed here indicated that integration of metabonomics with other techniques will be useful for better understanding the biochemistry of pathogenesis and progression of leukemia.

Integrating a prospective pilot trial and patient-derived xenografts to trace metabolic changes associated with acute myeloid leukemia

“…The increased lactate level in the plasma is a typical hallmark of cancer, characterized by an aerobic glycolytic shift (“Warburg effect”) [1, 12]. Lower plasma levels of cholesterol, lipids, and unsaturated fatty acids were found in AML mice than in healthy controls, in agreement with previous reports [6, 13, 14], highlighting an involvement of fatty acid metabolisms in AML, possibly related to the demand for lipids and cholesterol in tumor proliferation. Also, the increase of glutamine in AML mice is consistent with cancer since glutamine is a major carbon and nitrogen source for tumor cell proliferation [15].…”

“…Although the limited number of cases investigated in this study does not allow a meaningful comparison to previous reports [6, 7], the technical robustness and reproducibility of NMR, together with the minimal sample manipulations and invasiveness of this technique, appear well suited to perform longitudinal studies in clinical settings. Moreover, we first provide experimental evidence on how patient-derived xenografts can be integrated into metabolomic studies, complementing and narrowing the screening of clinically relevant metabolites.…”

“…Oncometabolites have been demonstrated in 5–20 % of AML-harboring mutations in Isocitrate Dehydrogenase (IDH) genes [2, 3], and the metabolic profile of AML cell lines can be employed to investigate drug treatments [4, 5]. Moreover, previous studies linked AML with perturbation of metabolic pathways including glucose metabolism [6, 7]. Nuclear magnetic resonance (NMR) is a rapid, highly reproducible cost-effective analytical tool to profile metabolic fluctuations, requiring minimal sample manipulation and well suited for automation and high-throughput purposes, thus ideal for untargeted analysis in clinical applications [8–11].…”

Investigation into Variation of Endogenous Metabolites in Bone Marrow Cells and Plasma in C3H/He Mice Exposed to Benzene

“…The increased bone marrow cell levels of phenylalanine may enhance the metabolic pathway from phenylalanine to tyrosine, resulting in a high concentration of bone marrow cell tyrosine. Higher serum levels of phenylalanine and tyrosine were observed in AML patients, which might be the result of enhanced degradation of proteins from the host experiencing a cancerous condition, and these two amino acids are needed for gluconeogenesis and for catabolism to provide intermediates for the tricarboxylic acid cycle (TCA) cycle [30]. It is possible that the toxicity to bone marrow with benzene exposure may be involved in the TCA cycle in mitochondria.…”

Synergistic cell death in FLT3-ITD positive acute myeloid leukemia by combined treatment with metformin and 6-benzylthioinosine

“…Acute myeloid leukemia (AML) is the most common myeloid neoplasm in adults and overall cure rates are low at 30–40% with relapse being a major cause of mortality [4]. Metabolomic analysis has identified key differences in the glycolytic, gluconeogenic, and tri-carboxylic acid (TCA) pathways between normal and AML cells [5, 6]. AML cells use abnormally high amounts of glucose from their microenvironment and exhibit high levels of glycolysis.…”