Annals of hematology
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Annals of hematology · Dec 2005
Clinical implications of aberrant DNA methylation patterns in acute myelogenous leukemia.
Hypermethylation of CpG islands near gene promoter regions is associated with transcriptional inactivation and represents an important mechanism of gene silencing in carcinogenesis. Such epigenetic phenomena can act alongside DNA mutations and deletions to disrupt tumor-suppressor gene function. The methylation status of the promoter-associated CpG islands from 11 well-characterized cancer-related genes was analyzed by methylation-specific polymerase chain reaction in 60 adult patients with acute myelogenous leukemia (AML) at diagnosis. ⋯ Our data indicate that hypermethylation of multiple genes involving fundamental cellular pathways is a common event in AML, which varies greatly in frequency among the genes examined. The accumulation of epigenetic events affecting genes which are involved in regulating cell cycle inhibition, cell adhesion, growth factor signaling, and apoptosis may contribute to the malignant AML phenotype. The growing knowledge of the role of epigenetics in the aberrant silencing of cancer-related genes provides a rationale and molecular basis for targeted therapeutic approaches with demethylating agents in AML.
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Annals of hematology · Dec 2005
Butyrates and decitabine cooperate to induce histone acetylation and granulocytic maturation of t(8;21) acute myeloid leukemia blasts.
Core histones are proteins organized in octamers, to which DNA is wrapped more or less tightly, depending on their acetylation status. Gene transcription is regulated by a complex series of epigenetic modifications, i.e., histone modification such as methylation and acetylation, events determined by the enzymatic activity of histone methyltransferases, and histone acetyltransferases, respectively, the latter counterbalanced by histone deacetylases (HDAC). Acetylation of histones facilitates destabilization of DNA-nucleosome interaction and renders DNA more accessible to transcription factors. ⋯ Histone acetylation as measured by flow cytometry was increased following treatment with D1 and the combination of D1 and decitabine. Addition of D1 alone or in combination with decitabine also led to inhibition of cell proliferation and induction of apoptosis. Thus, treatment of AML with HDAC inhibitors such as D1 and DNMT inhibitors such as decitabine might have clinical benefit for patients, especially these presenting subtypes of AML, like AML1/ETO, in which the leukemogenic mechanism involves corepressor protein complexes containing HDAC and DNMT.