Hypermethylation of Wnt antagonist gene promoters and activation of Wnt pathway in myelodysplastic marrow cells

Erico Masala; Ana Valencia; Francesca Buchi; Daniele Nosi; Elena Spinelli; Antonella Gozzini; Francesca Sassolini; Alessandro Sanna; Sandra Zecchi; Alberto Bosi; Valeria Santini

doi:10.1016/j.leukres.2012.05.023

Hypermethylation of Wnt antagonist gene promoters and activation of Wnt pathway in myelodysplastic marrow cells

Leuk Res. 2012 Oct;36(10):1290-5. doi: 10.1016/j.leukres.2012.05.023. Epub 2012 Jun 27.

Authors

Erico Masala¹, Ana Valencia, Francesca Buchi, Daniele Nosi, Elena Spinelli, Antonella Gozzini, Francesca Sassolini, Alessandro Sanna, Sandra Zecchi, Alberto Bosi, Valeria Santini

Affiliation

¹ UF Ematologia, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy.

PMID: 22742816
DOI: 10.1016/j.leukres.2012.05.023

Abstract

We observed aberrant gene methylation of Wnt antagonists: sFRP1, sFRP2, sFRP4, sFRP5 and DKK1 in marrow cells of 55 MDS cases. Methylation of Wnt antagonist genes was associated with activation of the Wnt signaling pathway, consistent with the up-regulation of the Wnt downstream genes TCF1 and LEF1. Azacitidine exposure induced demethylation of Wnt-antagonist gene promoters and reduction of the non-phosphorylated β-catenin (NPBC) which is prevalent during Wnt pathway inactivation. Presence of ≥5% of bone marrow blasts was associated with methylation of sFRP1 and DKK1 and with methylation of more than two of the five Wnt antagonist genes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Antimetabolites, Antineoplastic / pharmacology
Ataxia Telangiectasia Mutated Proteins
Azacitidine / pharmacology
Bone Marrow Cells / metabolism*
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Line, Tumor
DNA Methylation*
Female
Hepatocyte Nuclear Factor 1-alpha / genetics
Hepatocyte Nuclear Factor 1-alpha / metabolism
Humans
Immunoenzyme Techniques
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism
Lymphoid Enhancer-Binding Factor 1 / genetics
Lymphoid Enhancer-Binding Factor 1 / metabolism
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism
Middle Aged
Myelodysplastic Syndromes / genetics*
Myelodysplastic Syndromes / metabolism
Prognosis
Promoter Regions, Genetic / genetics*
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Signal Transduction
Wnt Proteins / antagonists & inhibitors*
Wnt Proteins / genetics
Wnt Proteins / metabolism
Wnt Signaling Pathway*

Substances

Antimetabolites, Antineoplastic
Cell Cycle Proteins
DKK1 protein, human
HNF1A protein, human
Hepatocyte Nuclear Factor 1-alpha
Intercellular Signaling Peptides and Proteins
LEF1 protein, human
Lymphoid Enhancer-Binding Factor 1
Membrane Proteins
Proto-Oncogene Proteins
RNA, Messenger
SFRP2 protein, human
SFRP4 protein, human
Wnt Proteins
ATR protein, human
Ataxia Telangiectasia Mutated Proteins
Protein Serine-Threonine Kinases
Azacitidine