Epigenetic risk stratification in juvenile myelomonocytic leukemia by targeted methylation analysis of the BMP4 locus
Year: 2025
Type: article
Study design: Observational Study
Abstract: Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myelodysplastic/myeloproliferative neoplasm characterized by distinct epigenetic signatures that facilitate molecular classification. This study aimed to evaluate the diagnostic utility of locus-specific DNA methylation in the bone morphogenetic protein 4 (BMP4) gene as a single predictor of disease outcomes in a cohort of 111 children diagnosed with JMML, alongside 9 healthy controls. Methylation levels of BMP4, assessed through targeted bisulfite next-generation sequencing (bs-NGS), were heterogeneous within the JMML cohort and were significantly associated with clinical risk factors, such as patient age, and fetal hemoglobin (HbF) levels. A comparative analysis of BMP4 bs-NGS and genome-wide methylation array data revealed a strong positive correlation (p < 0.001). The sensitivity and specificity of BMP4 bs-NGS for classifying high-methylation cases were 0.612 and 0.887, respectively. For PTPN11-mutant patients (N = 40), the sensitivity was 0.667 and the specificity was 0.842. Survival analysis indicated that patients with high BMP4 methylation (BMP4h) had lower 5-year disease-free survival (DFS) rates than those with normal BMP4 methylation (BMP4n). Specifically, the 20% of patients with highest BMP4 methylation had a 5-year DFS of 0.38, in contrast to 0.62 for the lowest 20% (p = 0.007). These findings highlight the potential of BMP4 methylation analysis as a complementary biomarker for JMML risk stratification, mirroring genome-wide methylation profiles known to associate with prognostic subgroups.
Source: Clinical Epigenetics
Authors: Foued Ghanjati, Annika Heck, Dirk Lebrecht, Peter Nöllke, Felicia Andresen, Natalia Rotari, Marlou Schoof, Maximilian Schönung, Daniel B. Lipka, Michael Dworzak, Barbara De Moerloose, Martina Sukova, Henrik Hasle, Kirsi Jahnukainen, Andrea Malone, Riccardo Masetti, Jochen Buechner, Marek Ussowicz, Albert Catala, Dominik Turkiewicz, Valérie de Haas, Markus Schmugge, Miriam Erlacher, Charlotte M. Niemeyer, Christian Flotho
Institutions: University of Freiburg, University Medical Center Freiburg, German Cancer Research Center, Heidelberg University, University Hospital Heidelberg, National Center for Tumor Diseases, Deutsches Konsortium für Translationale Krebsforschung, St Anna Children's Hospital, St. Anna Children's Cancer Research Institute, Medical University of Vienna, Ghent University Hospital, Charles University, University Hospital in Motol, Aarhus University Hospital, University of Helsinki, Helsinki University Hospital, Helsinki Children's Hospital, Children's Health Ireland at Crumlin, Oslo University Hospital, University of Wrocław, Wroclaw Medical University, Hospital Sant Joan de Déu Barcelona, Skåne University Hospital, Princess Máxima Center, University Children's Hospital Zurich
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,890
Funder: Deutsche Forschungsgemeinschaft
OpenAlex ID: W4414797013