Epigenetic regulation in myelodysplastic syndromes: implications for therapy.

Abstract

INTRODUCTION:

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.

AREAS COVERED:

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.

EXPERT OPINION:

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.

• Authors: Ernesto Vigna, Anna Grazia Recchia, Antonio Madeo, Massimo Gentile, Sabrina Bossio, Carla Mazzone, Eugenio Lucia, Lucio Morabito, Vincenzo Gigliotti, Laura De Stefano, Nadia Caruso, Pasquale Servillo, Stefania Franzese, Filippo Fimognari, Maria Grazia Bisconte, Carlo Gentile, Fortunato Morabito
• Journal: Expert opinion on investigational drugs (Expert Opin Investig Drugs) Vol. 20 Issue 4 Pg. 465-93 (Apr 2011) ISSN: 1744-7658 [Electronic] England
• PMID: 21381982 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antimetabolites, Antineoplastic
• Drugs, Investigational
• Histone Deacetylase Inhibitors

Topics

• Animals
• Antimetabolites, Antineoplastic (administration & dosage, 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, physiology)
• Gene Expression Regulation, Leukemic (drug effects)
• Histone Deacetylase Inhibitors (administration & dosage, therapeutic use)
• Humans
• Models, Biological
• Myelodysplastic Syndromes (drug therapy, genetics, physiopathology)