Aberrant DNA methylation profile of chronic and transformed classic Philadelphia-negative myeloproliferative neoplasms
Cristina Pérez,
Marien Pascual,
José Ignacio Martín-Subero,
Beatriz Bellosillo,
Victor Segura,
Eric Delabesse,
Sara Álvarez,
María José Larrayoz,
José Rifón,
Juan Cruz Cigudosa,
Carles Besses,
María José Calasanz,
Nicholas C.P. Cross,
Felipe Prósper,
Xabier Agirre
Affiliations
Cristina Pérez
Laboratory of Myeloproliferative Syndromes, Oncology Area, University of Navarra, Pamplona, Spain
Marien Pascual
Laboratory of Myeloproliferative Syndromes, Oncology Area, University of Navarra, Pamplona, Spain
José Ignacio Martín-Subero
Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain
Beatriz Bellosillo
Department of Pathology, Hospital del Mar, Barcelona, Spain
Victor Segura
Department of Bioinformatics, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain
Eric Delabesse
CHU Toulouse, Laboratoire d’Hematologie, Hôpital Purpan, Inserm U1037, University Paul Sabatier, Toulouse, France
Sara Álvarez
Molecular Cytogenetics Group. Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
María José Larrayoz
Department of Genetics, University of Navarra, Spain
José Rifón
Hematology Service and Area of Cell Therapy, Clínica Universidad de Navarra, University of Navarra, Spain
Juan Cruz Cigudosa
Molecular Cytogenetics Group. Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
Carles Besses
Department of Hematology, Hospital del Mar, Barcelona, Spain
María José Calasanz
Department of Genetics, University of Navarra, Spain
Nicholas C.P. Cross
Wessex Regional Genetics Laboratory, Salisbury, UK and Faculty of Medicine, University of Southampton, UK
Felipe Prósper
Laboratory of Myeloproliferative Syndromes, Oncology Area, University of Navarra, Pamplona, Spain;Hematology Service and Area of Cell Therapy, Clínica Universidad de Navarra, University of Navarra, Spain
Xabier Agirre
Laboratory of Myeloproliferative Syndromes, Oncology Area, University of Navarra, Pamplona, Spain
Most DNA methylation studies in classic Philadelphia-negative myeloproliferative neoplasms have been performed on a gene-by-gene basis. Therefore, a more comprehensive methylation profiling is needed to study the implications of this epigenetic marker in myeloproliferative neoplasms. Here, we have analyzed 71 chronic (24 polycythemia vera, 23 essential thrombocythemia and 24 primary myelofibrosis) and 13 transformed myeloproliferative neoplasms using genome-wide DNA methylation arrays. The three types of chronic Philadelphia-negative myeloproliferative neoplasms showed a similar aberrant DNA methylation pattern when compared to control samples. Differentially methylated regions were enriched in a gene network centered on the NF-κB pathway, indicating that they may be involved in the pathogenesis of these diseases. In the case of transformed myeloproliferative neoplasms, we detected an increased number of differentially methylated regions with respect to chronic myeloproliferative neoplasms. Interestingly, these genes were enriched in a list of differentially methylated regions in primary acute myeloid leukemia and in a gene network centered around the IFN pathway. Our results suggest that alterations in the DNA methylation landscape play an important role in the pathogenesis and leukemic transformation of myeloproliferative neoplasms. The therapeutic modulation of epigenetically-deregulated pathways may allow us to design targeted therapies for these patients.
