Epigenetic regulation in myelodysplastic syndromes: implications for therapy

• Published in: Expert opinion on investigational drugs Vol. 20; no. 4; p. 465
• Main Authors: Vigna, Ernesto, Recchia, Anna Grazia, Madeo, Antonio, Gentile, Massimo, Bossio, Sabrina, Mazzone, Carla, Lucia, Eugenio, Morabito, Lucio, Gigliotti, Vincenzo, Stefano, Laura De, Caruso, Nadia, Servillo, Pasquale, Franzese, Stefania, Fimognari, Filippo, Bisconte, Maria Grazia, Gentile, Carlo, Morabito, Fortunato
• Format: Journal Article
• Language: English
• Published: England 01.04.2011
• Subjects: Animals; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Clinical Trials as Topic; DNA Methylation - drug effects; Drug Evaluation, Preclinical; Drugs, Investigational - therapeutic use; Epigenesis, Genetic - drug effects; Epigenesis, Genetic - physiology; Gene Expression Regulation, Leukemic - drug effects; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - therapeutic use; Humans; Models, Biological; Myelodysplastic Syndromes - drug therapy; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - physiopathology
• ISSN: 1744-7658
• DOI: 10.1517/13543784.2011.559164

Myelodysplastic syndromes (MDS), characterized by ineffective hematopoiesis and dysplasia in one or more lineages, produce life-threatening cytopenias and progress to acute myeloid leukemia (AML). Growing evidence suggests that targeting epigenetic mechanisms improves MDS/AML pathophysiology. This review provides an understanding of studies investigating novel agents published up to January 2011 aimed at normalizing and monitoring the epigenetic profile of the MDS cancer cell. The authors discuss how non-intensive epigenetic therapy can 're-programme' gene expression patterns of abnormal hematopoiesis in MDS. Recently FDA-approved DNA-methyltransferase inhibitors, 5-azacytidine and 5-aza-2'-deoxycytidine or decitabine, represent frontline nonablative treatments, while combinations with histone deacetylase inhibitors show promising synergism in preclinical and Phase I/II trials in tumor suppressor gene re-expression and overall survival. Additional epigenetic mechanisms including non-encoding transcripts with inhibitory posttranscriptional regulatory functions, such as microRNAs, though not fully understood, present novel molecular and clinical implications in these disorders. Alongside current single-agent epigenetic regimens, combination therapies represent potentially effective options for intermediate-2 and high-risk MDS. Methylation profiles and gene mutation predictors provide promising areas of development for monitoring MDS disease progression and outcome, while targeting microRNA dysregulation represents an important therapeutic goal.