Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Homoharringtonine (HHT) has been widely used in China to treat patients with acute and chronic myeloid leukemia for decades. Since response to HHT varies among patients, our study aimed to identify biomarkers that might influence the response to HHT using a panel of various human lymphoblastoid cell lines (LCLs). Genome-wide association (GWA) analysis using single nucleotide polymorphism (SNP) and mRNA expression data was assessed for association with cytotoxicity to HHT in LCLs. Integrated analysis among SNPs, expression, AUC value was also performed to help select candidate genes for further functional characterization. Functional validation of candidate genes was performed using leukemia cell lines (U937, K562). Candidate genes were knocked down using specific siRNA and its response to HHT was assessed using MTS assay. We found that 15 expression probes were associated with HHT AUC with P < 10(-4), and 96 individual probe sets with P < 10(-3). Eighteen SNPs were associated with HHT AUC with P < 10(-5) and 281 SNPs with P < 10(-4). The integrated analysis identified 4 unique SNPs that were associated with both expression and AUC. Functional validation using siRNA knockdown in leukemia cell lines showed that knocking down CCDC88A, CTBP2, SOCS4 genes in U937 and K562 cells significantly altered HHT cytotoxicity. In summary, this study performed with LCLs can help to identify novel biomarker that might contribute to variation in response to HHT therapy.
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PMID:Identification of genetic variants or genes that are associated with Homoharringtonine (HHT) response through a genome-wide association study in human lymphoblastoid cell lines (LCLs). 2562 45

B cell chronic lymphocytic leukemia (B-CLL), the most common type of leukemia in adults, is still essentially incurable despite the development of novel therapeutic strategies. This reflects the incomplete understanding of the pathophysiology of this disease. A comprehensive proteome analysis of primary human B-CLL cells and B cells from younger as well as elderly healthy donors was performed. For comparison, the chronic B cell leukemia cell line JVM-13 was also included. A principal component analysis comprising 6,945 proteins separated these four groups, placing B cells of aged-matched controls between those of young donors and B-CLL patients, while identifying JVM-13 as poorly related cells. Mass spectrometric proteomics data have been made fully accessible via ProteomeXchange with identifier PXD006570-PXD006572, PXD006576, PXD006578, and PXD006589-PXD006591. Remarkably, B cells from aged controls displayed significant regulation of proteins related to stress management in mitochondria and ROS stress such as DLAT, FIS1, and NDUFAB1, and DNA repair, including RAD9A, MGMT, and XPA. ROS levels were indeed found significantly increased in B cells but not in T cells or monocytes from aged individuals. These alterations may be relevant for tumorigenesis and were observed similarly in B-CLL cells. In B-CLL cells, some remarkable unique features like the loss of tumor suppressor molecules PNN and JARID2, the stress-related serotonin transporter SLC6A4, and high expression of ZNF207, CCDC88A, PIGR and ID3, otherwise associated with stem cell phenotype, were determined. Alterations of metabolic enzymes were another outstanding feature in comparison to normal B cells, indicating increased beta-oxidation of fatty acids and increased consumption of glutamine. Targeted metabolomics assays corroborated these results. The present findings identify a potential proteome signature for immune senescence in addition to previously unrecognized features of B-CLL cells and suggest that aging may be accompanied by cellular reprogramming functionally relevant for predisposing B cells to transform to B-CLL cells.
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PMID:Proteomics and metabolomics identify molecular mechanisms of aging potentially predisposing for chronic lymphocytic leukemia. 2919 38