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Epigenetic regulation of tumorigenesis
Epigenetic modifications of DNA and histones have been implicated in cellular differentiation and tumorigenesis for quite some time. Recently however new light is being shed onto the importance of epigenetic modifications in tumor development as mutations identified in human gliomas and acute myeloid leukemia (AML) in the IDH1 and IDH2 genes result in enzymes with an aberrant enzymatic activity that influences epigenetics both on the DNA as well as on the histone level. Strikingly, these mutations result in the phenomenon that tumor entities can be subgrouped according to their epigenetic profiles. This has been shown for both glioblastoma (Noushmehr H et al., 2010), the most frequent and most malignant brain tumor in adults, as well as for AML (Figueroa M et al., 2010).
Characterization of cellular and epigenetic changes induced by mutant Idh1To analyze the impact of the IDH1/IDH2 mutations we generated a conditional KI mouse, which expresses one of the common mutations (R132H in Idh1). While it has been shown that mutant Idh proteins are able to alter the epigenetic landscape in human tumors the actual direct cellular outcome as well as the genetic targets are unclear. Our studies focus on how and through dysregulation of which genes mutant Idh1 influences cellular proliferation and differentiation both of normal, non-tumorigenic stem and progenitor cells as well as of tumor (stem) cells.
- Sasaki M, Knobbe CB, Itsumi M, Elia AJ, Harris IS, Chio II, Cairns RA, McCracken S, Wakeham A, Haight J, Ten AY, Snow B, Ueda T, Inoue S, Yamamoto K, Ko M, Rao A, Yen KE, Su SM, Mak TW. D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev. 26(18):2038-49, 2012. PubMed
- Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brüstle A, Harris IS, Holmes R, Wakeham A, Haight J, You-Ten A, Li WY, Schalm S, Su SM, Virtanen C, Reifenberger G, Ohashi PS, Barber DL, Figueroa ME, Melnick A, Zúñiga-Pflücker JC, Mak TW. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature. 488(7413):656-9, 2012. PubMed
- Knobbe CB, Revett TJ, Bai Y, Chow V, Jeon AH, Böhm C, Ehsani S, Kislinger T, Mount HT, Mak TW, St George-Hyslop P, Schmitt-Ulms G. Choice of Biological Source Material Supersedes Oxidative Stress in Its Influence on DJ-1 in Vivo Interactions with Hsp90. J Proteome Res. 10: 4388-4404, 2011. PubMed
- Knobbe CB, Reifenberger J, Blaschke B, Reifenberger G. Hypermethylation and transcriptional downregulation of the carboxyl-terminal modulator protein gene in glioblastomas. J Natl Cancer Inst. 96: 483-486, 2004. PubMed
- Knobbe CB, Reifenberger G. Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3'-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. Brain Pathol. 13: 507-518, 2003. PubMed