A distinct glucose metabolism signature of acute myeloid leukemia with prognostic value.

Acute myeloid leukemia (AML) is a group of hematological malignancies with high heterogeneity. There is an increasing need to improve the risk stratification of AML patients, including those with normal cytogenetics, using molecular biomarkers. Here, we report a metabolomics study that identified a distinct glucose metabolism signature with 400 AML patients and 446 healthy controls. The glucose metabolism signature comprises a panel of 6 serum metabolite markers, which demonstrated prognostic value in cytogenetically normal AML patients. We generated a prognosis risk score (PRS) with 6 metabolite markers for each patient using principal component analysis. A low PRS was able to predict patients with poor survival independently of well-established markers. We further compared the gene expression patterns of AML blast cells between low and high PRS groups, which correlated well to the metabolic pathways involving the 6 metabolite markers, with enhanced glycolysis and tricarboxylic [corrected] acid cycle at gene expression level in low PRS group. In vitro results demonstrated enhanced glycolysis contributed to decreased sensitivity to antileukemic agent arabinofuranosyl cytidine (Ara-C), whereas inhibition of glycolysis suppressed AML cell proliferation and potentiated cytotoxicity of Ara-C. Our study provides strong evidence for the use of serum metabolites and metabolic pathways as novel prognostic markers and potential therapeutic targets for AML.

Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China.

The 2-hydroxyglutarate (2-HG) has been reported to result from mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes and to function as an "oncometabolite." To evaluate the clinical significance of serum 2-HG levels in hematologic malignancies, acute myeloid leukemia (AML) in particular, we analyzed this metabolite in distinct types of human leukemia and lymphoma and established the range of serum 2-HG in appropriate normal control individuals by using gas chromatograph-time-of-flight mass spectrometry. Aberrant serum 2-HG pattern was detected in the multicenter group of AML, with 62 of 367 (17%) patients having 2-HG levels above the cutoff value (2.01, log2-transformed from 4.03 µg/mL). IDH1/2 mutations occurred in 27 of 31 (87%) AML cases with very high 2-HG, but were observed only in 9 of 31 (29%) patients with moderately high 2-HG, suggesting other genetic or biochemical events may exist in causing 2-HG elevation. Indeed, glutamine-related metabolites exhibited a pattern in favor of 2-HG synthesis in the high 2-HG group. In AML patients with cytogenetically normal AML (n = 234), high 2-HG represented a negative prognostic factor in both overall survival and event-free survival. Univariate and multivariate analyses confirmed high serum 2-HG as a strong prognostic predictor independent of other clinical and molecular features. We also demonstrated distinct gene-expression/DNA methylation profiles in AML blasts with high 2-HG compared with those with normal ones, supporting a role that 2-HG plays in leukemogenesis.

A combined proteomics and metabolomics profiling of gastric cardia cancer reveals characteristic dysregulations in glucose metabolism.

Gastric cardia cancer (GCC), which occurs at the gastric-esophageal boundary, is one of the most malignant tumors. Despite its high mortality and morbidity, the molecular mechanism of initiation and progression of this disease is largely unknown. In this study, using proteomics and metabolomics approaches, we found that the level of several enzymes and their related metabolic intermediates involved in glucose metabolism were deregulated in GCC. Among these enzymes, two subunits controlling pyruvic acid efflux, lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase B (PDHB), were further analyzed in vitro. Either down-regulation of LDH subunit LDHA or overexpression of PDH subunit PDHB could force pyruvic acid into the Krebs cycle rather than the glycolysis process in AGS gastric cancer cells, which inhibited cell growth and cell migration. Our results reflect an important glucose metabolic signature, especially the dysregulation of pyruvic acid efflux in the development of GCC. Forced transition from glycolysis to the Krebs cycle had an inhibitory effect on GCC progression, providing potential therapeutic targets for this disease.

In Situ Construction of Bronze/Anatase TiO2 Homogeneous Heterojunctions and Their Photocatalytic Performances.

Photocatalytic degradation is one of the most promising emerging technologies for environmental pollution control. However, the preparation of efficient, low-cost photocatalysts still faces many challenges. TiO2 is a widely available and inexpensive photocatalyst material, but improving its catalytic degradation performance has posed a significant challenge due to its shortcomings, such as the easy recombination of its photogenerated electron-hole pairs and its difficulty in absorbing visible light. The construction of homogeneous heterojunctions is an effective means to enhance the photocatalytic performances of photocatalysts. In this study, a TiO2(B)/TiO2(A) homogeneous heterojunction composite photocatalyst (with B and A denoting bronze and anatase phases, respectively) was successfully constructed in situ. Although the construction of homogeneous heterojunctions did not improve the light absorption performance of the material, its photocatalytic degradation performance was substantially enhanced. This was due to the suppression of the recombination of photogenerated electron-hole pairs and the enhancement of the carrier mobility. The photocatalytic ability of the TiO2(B)/TiO2(A) homogeneous heterojunction composite photocatalyst was up to three times higher than that of raw TiO2 (pure anatase TiO2).

Use of the metabolomics approach to characterize Chinese medicinal material Huangqi.

Integration of the genetic and metabolic fingerprinting can provide a new approach to differentiate similar Traditional Chinese Medical (TCM) materials. Two leguminous plants, Mojia Huangqi and Menggu Huangqi, are important medical herbs and share great similarities in morphology, chemical constituent, and genomic DNA sequence. The taxonomy of Mojia Huangqi and Menggu Huangqi has been debated for more than 50 years and discrimination of TCM materials directly affects the pharmacological and clinical effects. AFLP based genetic fingerprinting and GC-TOF/MS-based metabolic fingerprinting were used to successfully discriminate the two species. The results of AFLP supported the opinion that Menggu Huangqi was a variant of Mojia Huangqi. The metabolic fingerprinting showed growth locations have greater impacts on the metabolite composition and quantity than the genotypes (cultivated versus wild) in Menggu Huangqi. The difference of some soluble sugars, fatty acids, proline, and polyamine reflected plant adaptation to different growth environments. Using multivariate and univariate statistical analysis, three AFLP markers and eight metabolites were identified as candidate DNA and metabolic markers to distinguish the two herb materials. The correlation network between AFLP markers and metabolites revealed a complex correlation network, which indicated the special metabolic pathways and the regulation networks of Huangqi.