Mutant IDH1 regulates the tumor-associated immune system in gliomas
| Autor: | Eric C. Holland, Mark L. Hanke, Daciana Margineantu, Jeff Delrow, Julia Kargl, A. McGarry Houghton, Nduka Amankulor, Sonali Arora, Aparna Rao, Frank Szulzewsky, David M. Hockenbery, Hamid Bolouri, Youngmi Kim |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
IDH1 Neutrophils Biology 03 medical and health sciences Mice Immune system Glioma Genetics medicine Leukocytes Animals Humans Microglia CpG Island Methylator Phenotype Brain Neoplasms Chemotaxis DNA Methylation medicine.disease Isocitrate Dehydrogenase Disease Models Animal 030104 developmental biology medicine.anatomical_structure Isocitrate dehydrogenase Neutrophil Infiltration Immune System DNA methylation Mutation Cancer research Leukocyte Common Antigens Leukocyte chemotaxis Developmental Biology Research Paper |
| Zdroj: | Genesdevelopment. 31(8) |
| ISSN: | 1549-5477 |
| Popis: | Gliomas harboring mutations in isocitrate dehydrogenase 1/2 (IDH1/2) have the CpG island methylator phenotype (CIMP) and significantly longer patient survival time than wild-type IDH1/2 (wtIDH1/2) tumors. Although there are many factors underlying the differences in survival between these two tumor types, immune-related differences in cell content are potentially important contributors. In order to investigate the role of IDH mutations in immune response, we created a syngeneic pair mouse model for mutant IDH1 (muIDH1) and wtIDH1 gliomas and demonstrated that muIDH1 mice showed many molecular and clinical similarities to muIDH1 human gliomas, including a 100-fold higher concentration of 2-hydroxygluratate (2-HG), longer survival time, and higher CpG methylation compared with wtIDH1. Also, we showed that IDH1 mutations caused down-regulation of leukocyte chemotaxis, resulting in repression of the tumor-associated immune system. Given that significant infiltration of immune cells such as macrophages, microglia, monocytes, and neutrophils is linked to poor prognosis in many cancer types, these reduced immune infiltrates in muIDH1 glioma tumors may contribute in part to the differences in aggressiveness of the two glioma types. |
| Databáze: | OpenAIRE |
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