Integrative Gene Expression Profiling Reveals G6PD-Mediated Resistance to RNA-Directed Nucleoside Analogues in B-Cell Neoplasms
| العنوان: | Integrative Gene Expression Profiling Reveals G6PD-Mediated Resistance to RNA-Directed Nucleoside Analogues in B-Cell Neoplasms |
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| المؤلفون: | Nancy L. Krett, Michael E Yarrington, Varsha Gandhi, Mala Shanmugam, Samuel K. McBrayer, Jun Qian, Steven T. Rosen, Gang Feng |
| المصدر: | PLoS ONE PLoS ONE, Vol 7, Iss 7, p e41455 (2012) |
| بيانات النشر: | Public Library of Science, 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Adenosine, 2-Chloroadenosine, Microarrays, Chronic lymphocytic leukemia, Cell, Cancer Treatment, lcsh:Medicine, Gene Expression, Lymphoma, Mantle-Cell, Biochemistry, Pentose Phosphate Pathway, 0302 clinical medicine, RNA interference, hemic and lymphatic diseases, Gene expression, Molecular Cell Biology, Basic Cancer Research, RNA, Neoplasm, lcsh:Science, Cancers and neoplasms, Non-Hodgkin lymphoma, Regulation of gene expression, 0303 health sciences, Multidisciplinary, Clinical Trials, Phase I as Topic, Neoplasm Proteins, Nucleic acids, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Hematologic Neoplasms, Carbohydrate Metabolism, Medicine, Lymphomas, Metabolic Pathways, Multiple Myeloma, Research Article, Biology, Glucosephosphate Dehydrogenase, Biosynthesis, Gene Expression Regulation, Enzymologic, Molecular Genetics, 03 medical and health sciences, Cell Line, Tumor, Leukemias, medicine, Humans, Myelomas and Lymphoproliferative Diseases, Nucleic Acid Components, B cell, 030304 developmental biology, Gene Expression Profiling, lcsh:R, Computational Biology, Chemotherapy and Drug Treatment, medicine.disease, Molecular biology, Leukemia, Lymphocytic, Chronic, B-Cell, Gene expression profiling, Metabolism, Cell culture, Drug Resistance, Neoplasm, Hematologic cancers and related disorders, Biocatalysis, RNA, lcsh:Q, Drug Screening Assays, Antitumor, Nucleoside |
| الوصف: | The nucleoside analogues 8-amino-adenosine and 8-chloro-adenosine have been investigated in the context of B-lineage lymphoid malignancies by our laboratories due to the selective cytotoxicity they exhibit toward multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL) cell lines and primary cells. Encouraging pharmacokinetic and pharmacodynamic properties of 8-chloro-adenosine being documented in an ongoing Phase I trial in CLL provide additional impetus for the study of these promising drugs. In order to foster a deeper understanding of the commonalities between their mechanisms of action and gain insight into specific patient cohorts positioned to achieve maximal benefit from treatment, we devised a novel two-tiered chemoinformatic screen to identify molecular determinants of responsiveness to these compounds. This screen entailed: 1) the elucidation of gene expression patterns highly associated with the anti-tumor activity of 8-chloro-adenosine in the NCI-60 cell line panel, 2) characterization of altered transcript abundances between paired MM and MCL cell lines exhibiting differential susceptibility to 8-amino-adenosine, and 3) integration of the resulting datasets. This approach generated a signature of seven unique genes including G6PD which encodes the rate-determining enzyme of the pentose phosphate pathway (PPP), glucose-6-phosphate dehydrogenase. Bioinformatic analysis of primary cell gene expression data demonstrated that G6PD is frequently overexpressed in MM and CLL, highlighting the potential clinical implications of this finding. Utilizing the paired sensitive and resistant MM and MCL cell lines as a model system, we go on to demonstrate through loss-of-function and gain-of-function studies that elevated G6PD expression is necessary to maintain resistance to 8-amino- and 8-chloro-adenosine but insufficient to induce de novo resistance in sensitive cells. Taken together, these results indicate that G6PD activity antagonizes the cytotoxicity of 8-substituted adenosine analogues and suggests that administration of these agents to patients with B-cell malignancies exhibiting normal levels of G6PD expression may be particularly efficacious. |
| اللغة: | English |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::752f1251a67801d206ba46615c257de6Test http://europepmc.org/articles/PMC3407247Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....752f1251a67801d206ba46615c257de6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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