Acute myeloid leukemia (AML) is a kind of hematological tumor with malignant proliferation of hematopoietic precursor cells in the bone marrow. It is a common leukemia with high mortality rate in adults. The incidence rate is about 100,000. At 4:50, the 5-year survival rate of patients after treatment is only 25-30%. In recent years, the incidence of AML has become younger and more prone, and there is an urgent need for more targeted target therapeutic drugs to improve the therapeutic effect and improve the prognosis of patients. We know that the glucose metabolism disorder dominated by glycolysis and tricarboxylic acid cycle is a major metabolic feature in the growth and proliferation of cancer cells. Isocitrate dehydrogenase (IDH) is a key enzyme in the Krebs cycle, which converts isocitrate to α-ketoglutarate (α-KG or 2-KG), IDH mutations This raises the level of a downstream metabolite called 2-hydroxyglutaric acid (2-HG). In recent years, IDH1/2 mutations have been found in a variety of tumors including leukemia and glioma. Studies have shown that mutations in this gene may be involved in the development of AML, in adult AML, especially in normal karyotype AML patients. The higher incidence is related to the treatment response of AML, leukemia residual, recurrence, etc. Different subtypes of IDH have different effects on the prognosis of adult AML. Because of the high degree of heterogeneity of leukemia, patients with different subtypes have large differences in prognosis risk. If the patient's prognosis risk can be predicted more accurately at the time of initial diagnosis, the doctor will adjust the treatment plan according to such patient classification to effectively improve the survival time of the patient with high prognosis risk. Previous studies have systematically analyzed AML from chromosomes, genes, and protein layers, and have produced a number of molecular markers based on their cellular and cytogenetic characteristics, which have been able to have high prognostic risk and unfavorable risk. , favorable risk) patients were classified. However, these cytogenetic methods cannot be evaluated and classified for patients with normal karyotypes (about 50% of AML), which means that doctors cannot treat the risk (recurrence and survival) of about half of AML patients. Evaluation, clinically, new molecular markers are still urgently needed to improve the prediction and classification system of AML treatment risk. With the deepening of the research, we found that the abnormally active glycolysis metabolism of AML cells can lead to a serious deficiency of glucose levels in the bone marrow microenvironment. In this case, how to maintain a sufficient amount of carbon source uptake by AML cells to maintain the malignant proliferation of cells may be a very important new mechanism of cancer metabolism. Studies driven by this new scientific hypothesis suggest that AML cells initiate an alternative mechanism to switch to fructose in the absence of glucose. Fructose is the second largest blood sugar in the human blood system, and its cellular transport is mediated by the GLUT5 protein transporter encoded by the SLC2A5 gene. In our study, we found that the higher the level of SLC2A5 gene expressed by AML cells, the stronger the ability to utilize fructose, the worse the patient's prognosis. The use of RNA silencing technology to interfere with SLC2A5 gene expression in AML cells significantly reduced the uptake of fructose by cells and fructose-induced cell proliferation. On this basis, we used a small molecule drug to specifically block the transmembrane transport of fructose. This method of inhibiting fructose utilization has been shown to significantly inhibit malignant proliferation and infiltration of cells in an in vitro cell model. In the AML animal model, the transmembrane transport of AML cells that block the fructose using this small molecule drug can significantly improve the leukemia symptoms and prolong the survival of mice. It is worth noting that the small molecule drug can also play a synergistic effect with the chemotherapeutic drug cytarabine, which can significantly improve the therapeutic effect of the chemotherapeutic drug. This research work was published online in November 2016 in the journal Cancer Research. Finally, summarize some of the new findings of our AML research and its implications. Due to metabolic mutations caused by mutations in the IDH1/2 gene, some of the AML patients have significantly higher levels of 2-HG in their serum than normal values. Such high serum 2-HG levels mean poor patient prognosis - easier to treat Post-recurrence and short survival. The combination of several key metabolites in the glycolysis process as a new means of detection can more accurately classify the prognosis of approximately 50% of AML patients, which previously could not be Risk characterization is performed using clinical cytogenetic methods. In addition to glucose, we have recently discovered that fructose is an important (alternative) energy source for AML cells. Therefore, the protein transporter GLUT5, which is responsible for fructose transport, is expected to be a new target for the treatment of AML. This characteristic fructose metabolism phenotype is likely to be present in other tumor cells other than AML. Small molecule chemical drugs or antibody drugs against GLUT5 are expected to be combined with current common tumor chemotherapy drugs (such as cytarabine). Use, greatly improve the treatment effect of cancer patients. These cancer metabolism-based transformation studies have also shown that metabolomics will play an increasingly important and leading role in medical fields such as clinical diseases and drug development. Original source: Source: Web of Science blog Jia Wei / Author: Jia Wei Tetanus Vaccine,Hepatitis B Vaccine For Adults,Tetanus Booster,Td Vaccine FOSHAN PHARMA CO., LTD. , https://www.fs-pharma.com
Professor Jia Wei led our research team to cooperate with the research team of Professor Chen Saijuan of Shanghai Institute of Hematology since 2012 to conduct systematic and in-depth metabolic research on AML. We used a metabolomics technique based on gas chromatography-time-of-flight mass spectrometry to quantify serum metabolites from a total of 772 samples of 367 patients with AML. Only 17% of serum 367 AML were found in 367 AML. Levels above normal indicate that oncometabolites due to IDH mutations are not a sensitive and accurate biomarker for AML development. Further analysis of the survival rate of patients with AML found that the higher the serum 2-HG level in patients, the worse the recurrence and survival after treatment, suggesting that 2-HG is more likely to be an effective prognostic factor for AML.
Molecularly, the IDH mutation causes more α-KG to be converted to 2-HG (R-type), which competes with α-KG, which reduces the activity of α-KG-dependent enzymes, resulting in a high chromatin The base, which interferes with normal cell differentiation, causes immature cells to proliferate and cause cancer. Therefore, intervention on the IDH1/2 mutation of cells may become an effective cancer treatment method. At present, several international research institutions and pharmaceutical companies are systematically developing small molecule inhibitors and gene antibodies of IDH1/2, hoping to launch A new anticancer drug based on the molecular target of IDH.
We continue to study the relationship between glucose metabolism and prognosis in patients with AML. The metabolic profiles of 229 AML patients and 260 healthy volunteers from Shanghai Ruijin Hospital were analyzed, and the most significant changes in glucose metabolism were found in lactic acid, α-ketoglutaric acid, 2-HG, pyruvic acid, and glycerol. A composition consisting of 6 small molecule metabolites of 3-phosphate and citric acid can better predict the prognosis of AML patients, especially those with normal karyotypes, and can be a biomarker for independent prediction of AML occurrence. The results of this study were validated in clinical samples from 171 AML patients and 186 healthy controls from a number of hematology centers in Hangzhou, Suzhou, Shenyang, Nanjing, Dalian, and Beijing. The metabolic levels of the composition (scores) The higher the prognosis, the worse the prognosis. Further studies have also shown that patients with high prognosis risk of AML not only have a significant increase in the glycolytic pathway and the tricarboxylic acid cycle pathway, but also a corresponding increase in key gene expression levels. In vitro cell research experiments have also revealed that enhancement of glycolysis is essential for malignant proliferation of AML cells, and such metabolic characteristics can also induce drug resistance in AML cells. 
Changes in metabolic levels of six small molecule metabolites (lactic acid, 2-KG, 2-HG, pyruvate, glycerol-3-phosphate, and citric acid) in glucose metabolism from clinical multicenter acute myeloid leukemia and healthy controls Heat map 
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