Epigenetic risk stratification in juvenile myelomonocytic leukemia by targeted methylation analysis of the BMP4 locus
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.
Authors
- Markus Schmugge (ORCID: https://orcid.org/0000-0003-4745-8572)
- Felicia Andresen
- Christian Flotho (ORCID: https://orcid.org/0000-0001-9367-0553)
- Martina Suková
- Miriam Erlacher (ORCID: https://orcid.org/0000-0002-7261-1447)
- Albert Català (ORCID: https://orcid.org/0000-0003-0133-1752)
- Daniel B. Lipka (ORCID: https://orcid.org/0000-0001-5081-7869)
- Dominik Turkiewicz
- Maximilian Schönung (ORCID: https://orcid.org/0000-0002-9778-9698)
- Marek Ussowicz (ORCID: https://orcid.org/0000-0001-5725-4835)
- Jochen Buechner (ORCID: https://orcid.org/0000-0001-5848-4501)
- Dirk Lebrecht (ORCID: https://orcid.org/0000-0002-4483-2920)
- Albert J. R. Heck (ORCID: https://orcid.org/0000-0002-2405-4404)
- Michael Schoof (ORCID: https://orcid.org/0000-0003-3531-5232)
- Michael Dworzak (ORCID: https://orcid.org/0000-0002-8175-1097)
- Foued Ghanjati (ORCID: https://orcid.org/0000-0002-4844-1564)
- Barbara De Moerloose (ORCID: https://orcid.org/0000-0002-2449-539X)
- Henrik Hasle (ORCID: https://orcid.org/0000-0003-3976-9231)
- Kirsi Jahnukainen
- Riccardo Masetti
- Natalia Rotari
- Válerie de Haas (ORCID: https://orcid.org/0000-0003-0339-6816)
- Peter Nöllke
- Charlotte M. Niemeyer
- Andrea Malone
Institutions
- Oslo University Hospital (NO)
- Hospital Sant Joan de Déu Barcelona (ES)
- University of Helsinki (FI)
- German Cancer Research Center (DE)
- Charles University (CZ)
- Heidelberg University (DE)
- Helsinki University Hospital (FI)
- Ghent University Hospital (BE)
- University Medical Center Freiburg (DE)
- University Hospital Heidelberg (DE)
- Aarhus University Hospital (DK)
- Wroclaw Medical University (PL)
- Helsinki Children's Hospital (FI)
- University Hospital in Motol (CZ)
- National Center for Tumor Diseases (DE)
- Azienda USL di Bologna (IT)
- St Anna Children's Hospital (AT)
- Princess Máxima Center (NL)
- University Children's Hospital Zurich (CH)
- Skåne University Hospital (SE)
- Our Lady's Hospital (IE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Epigenomics (Germany) (DE)
Publication Details
- Journal
- Clinical Epigenetics
- Published
- 2025-10-03
- DOI
- https://doi.org/10.1186/s13148-025-01983-0
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00