Targeting hypomethylation of DNA to achieve cellular differentiation in myelodysplastic syndromes (MDS).
Considerable progress has been made recently in defining and understanding the diverse members of the group of hematologic disorders now known as the myelodysplastic syndrome (MDS). New systems of classification, based on the latest cytogenetic methodologies, have generated better prognostic data, and basic research has more closely associated molecular mechanisms with clinical subgroups. The mechanisms underlying most cases of myelodysplasia appear to be an array of chromosomal abnormalities leading to suppression of normal myeloid cell differentiation and dominance of abnormal, immature cells. The process is progressive and is mediated by a variety of cytokines, potential loss of tumor suppressor genes, aberrations in signal transduction pathways, and perhaps immune mechanisms. Hypermethylation of specific DNA sequences has been implicated in the pathogenesis of MDS. Until recently, treatment options have been few, high risk, and mostly ineffective. New discoveries, particularly in the area of stimulating remaining normal myeloid cells to resume growth and differentiation, hold promise for safer treatment regimens and improved outcomes. Among the promising new agents are nucleoside analogues, such as 5-azacytidine and decitabine, which reactivate tumor suppressor gene transcription through effects on DNA methylation.
Silverman
L R
LR
Division of Medical Oncology, Mount Sinai School of Medicine, New York, New York 10029, USA. lewis.silverman@mssm.edu
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016207:Cytokines / Q000235:genetics; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D004273:DNA, Neoplasm / Q000187:drug effects*; D000077209:Decitabine; D006801:Humans; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics*; D022423:Myeloid Cells / Q000187:drug effects; D011379:Prognosis; D011788:Quality of Life
D000964:Antimetabolites, Antineoplastic; D016207:Cytokines; D004273:DNA, Neoplasm; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine