title: PDGFB hypomethylation is a favourable prognostic biomarker in primary myelofibrosis.
abstract: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterised by the clonal proliferation of the haematopoietic precursors together with the progressive development of bone marrow fibrosis. This stromal alteration is an important clinical issue and specific prognostic markers are not currently available. In bone marrow biopsies from 58 PMF patients, we explored the methylation pattern of genes encoding cytokines involved in the stromal reaction, namely platelet-derived growth factor-beta (PDGFB), transforming growth factor-beta (TGFB) and basic fibroblast growth factor (FGF2). We also evaluated the methylation profile of the Long Interspersed Nucleotide Element 1 (LINE-1). PDGFB, FGF2 and LINE-1, but not TGFB, were significantly differently methylated in PMF compared to controls. Significantly, PDGFB hypomethylation (<16%) was correlated with a favourable PMF prognosis (grade of marrow fibrosis, p=0.03; International Prognostic Scoring Systems p=0.01 and Dynamic International Prognostic Scoring Systems, p=0.02). Although the basis of the association of PDGFB hypomethylation with favourable prognosis remains to be clarified, we speculate that hypomethylation in PMF could represent the effect of acquired somatic mutations in genes involved in epigenetic regulation of the genome.
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Augello
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy; Hematopathology Section, Division of Pathology, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Gianelli
authors.affiliation: Division of Pathology, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico Milano, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Falcone
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Tabano
authors.affiliation: Division of Pathology, Ospedale San Paolo, Milano, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Savi
authors.affiliation: Division of Pathology, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico Milano, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Bonaparte
authors.affiliation: Division of Pathology, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico Milano, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Ciboddo
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy; Division of Pathology, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico Milano, Italy.
authors.forename: Leda
authors.initials: L
authors.lastname: Paganini
authors.affiliation: Pathology Department, Istituto Ortopedico G. Pini, Milano, Italy.
authors.forename: Antonina
authors.initials: A
authors.lastname: Parafioriti
authors.affiliation: Division of Pathology, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico Milano, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Ricca
authors.affiliation: Hematology and Transplantation Unit, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Policlinico, Milano, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lonati
authors.affiliation: Hematology and Transplantation Unit, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Policlinico, Milano, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cattaneo
authors.affiliation: Hematology and Transplantation Unit, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Policlinico, Milano, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.
authors.forename: Nicola Stefano
authors.initials: NS
authors.lastname: Fracchiolla
authors.affiliation: Oncohematology Unit of the Elderly, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico Milano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Iurlo
authors.affiliation: Hematology and Transplantation Unit, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Policlinico, Milano, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Cortelezzi
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy; Division of Pathology, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico Milano, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Bosari
authors.affiliation: Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy; Division of Pathology, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico Milano, Italy. Electronic address: monica.miozzo@unimi.it.
authors.forename: Monica
authors.initials: M
authors.lastname: Miozzo
authors.affiliation: Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Silvia Maria
authors.initials: SM
authors.lastname: Sirchia
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008875:Middle Aged; D055728:Primary Myelofibrosis / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics
chemical_list: D015415:Biomarkers; D020574:Proto-Oncogene Proteins c-sis; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2
keywords: DNA methylation; FGF2; LINE-1; PDGFB; Primary myelofibrosis