DNA hypermethylation of myeloid cells, a novel therapeutic target in MDS and AML.
Differential methylation of CpG islands is a regulatory mechanism for promoter activity of different classes of genes, including tissue-specific genes. These CpG islands are targets for transformation-associated, aberrant hypermethylation activity during leukemogenesis. Therefore the pharmacological reversion of this methylator phenotype (e.g. by reactivation of tumor suppressor gene expression) is an important rationale for development of inhibitors of DNA methyltransferase activity. In vitro, inhibition of methylation using azanucleosides results in modest differentiation of transformed myeloid cell lines. In vivo, low doses of these agents induce DNA demethylation of malignant myeloid cells. Indeed, the first drug specifically approved for the treatment of myelodysplastic syndrome (MDS) was the azanucleoside 5-azacytidine (Vidaza). The most potent DNA demethylating agent available, 5-aza-2' deoxycytidine (Decitabine, Dacogen) also has recently been approved by the U.S.A. FDA for treatment of MDS of all subtypes. About 30 % of MDS patients with an abnormal karyotype have normalization of their karyotype after receiving the drug. This activity is especially relevant in patients with high-risk karyotypic abnormalities (complex karyotype and/or abnormalities of chromosome 7) compared to patients with intermediate-risk karyotype. Both drugs offer a novel, non-intensive therapeutic approach, particularly in the older patient population who due to comorbidities and/or reduced performance status are ineligible for aggressive chemotherapies. Target genes being particularly prone to demethylation by these drugs in the aberrant cells (e.g. p15/INK4b) are under active investigation. Future translational and clinical studies will be aimed at improving the response rate and duration of response to non-intensive treatment with demethylating agents, by studying rational drug combinations e.g. with inhibitors of histone deacetylase activity.
Müller
Claudia I
CI
University of Freiburg Medical Center, Department Internal Medicine I, Div. Hematology/Oncology, Albert-Ludwigs-University, Hugstetter Str., D-79106 Freiburg, Germany.
Rüter
Björn
B
Koeffler
H Phillip
HP
Lübbert
Michael
M
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018899:CpG Islands / Q000187:drug effects* / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D016503:Drug Delivery Systems / Q000379:methods*; D018390:Gene Targeting / Q000379:methods; D006801:Humans; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics; D022423:Myeloid Cells / Q000187:drug effects*; D009705:Nucleosides / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D009705:Nucleosides