Abstract
BackgroundPatients suffering from the BCR-ABL1-negative myeloproliferative disease prefibrotic primary myelofibrosis (pre-PMF) have a certain risk for progression to myelofibrosis. Accurate risk estimation for this fibrotic progression is of prognostic importance and clinically relevant. Commonly applied risk scores are based on clinical, cytogenetic, and genetic data but do not include epigenetic modifications. Therefore, we evaluated the assessment of genome-wide DNA methylation patterns for their ability to predict fibrotic progression in PMF patients.ResultsFor this purpose, the DNA methylation profile was analyzed genome-wide in a training set of 22 bone marrow trephines from patients with either fibrotic progression (n = 12) or stable disease over several years (n = 10) using the 850 k EPIC array from Illumina. The DNA methylation classifier constructed from this data set was validated in an independently measured test set of additional 11 bone marrow trephines (7 with stable disease, 4 with fibrotic progress). Hierarchical clustering of methylation β-values and linear discriminant classification yielded very good discrimination between both patient groups. By gene ontology analysis, the most differentially methylated CpG sites are primarily associated with genes involved in cell–cell and cell–matrix interactions.ConclusionsIn conclusion, we could show that genome-wide DNA methylation profiling of bone marrow trephines is feasible under routine diagnostic conditions and, more importantly, is able to predict fibrotic progression in pre-fibrotic primary myelofibrosis with high accuracy.
Highlights
Primary myelofibrosis (PMF) belongs to the BCR/ABL1negative myeloproliferative neoplasms and is often characterized by a bi-phasic course of disease
Suitability of routinely processed FFPE bone marrow trephines for genome‐wide DNA methylation analyses In a first step, we analyzed 4 samples using the Illumina EPIC array in order to figure out whether the amount and quality of genomic DNA extracted from the routinely processed, fixed, decalcified, and embedded bone marrow trephines in our institution provide a reliable and evaluable signal output
The amount of genomic DNA used for DNA methylation analysis and the age of the sample could be excluded as confounding factors in our series of altogether 33 samples
Summary
Primary myelofibrosis (PMF) belongs to the BCR/ABL1negative myeloproliferative neoplasms and is often characterized by a bi-phasic course of disease. The disease manifests itself with thrombocytosis and granulocytosis without bone marrow fibrosis [1, 2]. This phase can last for years (stable disease). The duration of stable disease and the risk to fibrotic progression varies substantially between individual patients [3]. Considering the considerable risk connected with HSCT [4, 5], the proper identification of patients with higher risk of fibrotic progression is of utmost importance. Patients suffering from the BCR-ABL1-negative myeloproliferative disease prefibrotic primary myelofibrosis (pre-PMF) have a certain risk for progression to myelofibrosis. Accurate risk estimation for this fibrotic progression is of prognostic importance and clinically relevant. We evaluated the assessment of genome-wide DNA methylation patterns for their ability to predict fibrotic progression in PMF patients
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