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.

Department of Hematology and Oncology Hospital Sant Joan de Deu Barcelona Spain

Department of Hematology and Oncology University Children's Hospital Zurich Switzerland

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Paediatric Haematology Oncology Ghent University Hospital Ghent Belgium

Department of Pediatric Hematology and Oncology BMT Unit CIC 817 Wroclaw Medical University Wrocław Poland

Department of Pediatric Hematology and Oncology Children's Hospital Medical Center Faculty of Medicine University of Freiburg Freiburg Germany

Department of Pediatric Hematology and Oncology Oslo University Hospital Oslo Norway

Department of Pediatrics Aarhus University Hospital Aarhus Denmark

Department of Pediatrics Section of Pediatric Oncology Hematology Immunology and Nephrology Skåne University Hospital Lund Sweden

Division of Hematology Oncology and SCT Children´S Hospital University of Helsinki and Helsinki University Hospital Helsinki Finland

Dutch Childhood Oncology Group Princess Máxima Center for Pediatric Oncology Utrecht Netherlands

German Cancer Consortium DKFZ Core Center Heidelberg Germany

German Cancer Consortium Partner Site Freiburg a partnership between DKFZ and University Medical Center Freiburg Germany

National Center for Tumor Diseases NCT Heidelberg a partnership between DKFZ and Heidelberg University Hospital Heidelberg Germany

Pediatric Haematology Our Lady's Children's Hospital Dublin Ireland

Pediatric Oncology and Haematology IRCCS Azienda Ospedaliero Universitaria Di Bologna Bologna Italy

Section of Translational Cancer Epigenomics Division of Translational Medical Oncology German Cancer Research Center Heidelberg Germany

St Anna Children's Hospital Department of Pediatrics and Adolescent Medicine Anna Children's Cancer Research Institute Medical University of Vienna and St Vienna Austria

Zobrazit více v PubMed

Niemeyer CM, Flotho C. Juvenile myelomonocytic leukemia: who’s the driver at the wheel? Blood. 2019;133(10):1060–70. PubMed DOI

Niemeyer, C.M., et al. 1997 PubMed

Locatelli F, et al. Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG MDS/EBMT trial. Blood. 2005;105(1):410–9. PubMed DOI

Flotho C, et al. RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). Leukemia. 1999;13(1):32–7. PubMed DOI

Sakaguchi H, et al. Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet. 2013;45(8):937–41. PubMed DOI

Hofmans M, et al. The long non-coding RNA landscape in juvenile myelomonocytic leukemia. Haematologica. 2018;103(11):e501–4. PubMed DOI PMC

Caye A, et al. Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet. 2015;47(11):1334–40. PubMed DOI

Murakami N, et al. Integrated molecular profiling of juvenile myelomonocytic leukemia. Blood. 2018;131(14):1576–86. PubMed DOI

Stieglitz E, et al. Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia. Nat Commun. 2017;8(1):2127. PubMed DOI PMC

Lipka DB, et al. RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia. Nat Commun. 2017;8(1):2126. PubMed DOI PMC

Schonung M, et al. International consensus definition of DNA methylation subgroups in juvenile myelomonocytic leukemia. Clin Cancer Res. 2021;27(1):158–68. PubMed DOI PMC

Olk-Batz C, et al. Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome. Blood. 2011;117(18):4871–80. PubMed DOI

Chang H, Brown CW, Matzuk MM. Genetic analysis of the mammalian transforming growth factor-beta superfamily. Endocr Rev. 2002;23(6):787–823. PubMed DOI

Kawabata M, Imamura T, Miyazono K. Signal transduction by bone morphogenetic proteins. Cytokine Growth Factor Rev. 1998;9(1):49–61. PubMed DOI

Sadlon TJ, Lewis ID, D’Andrea RJ. BMP4: its role in development of the hematopoietic system and potential as a hematopoietic growth factor. Stem Cells. 2004;22(4):457–74. PubMed DOI

Goldman DC, et al. BMP4 regulates the hematopoietic stem cell niche. Blood. 2009;114(20):4393–401. PubMed DOI PMC

Jeong S, et al. BMP4 and perivascular cells promote hematopoietic differentiation of human pluripotent stem cells in a differentiation stage-specific manner. Exp Mol Med. 2020;52(1):56–65. PubMed DOI PMC

Mayerhofer C, Niemeyer CM, Flotho C. Current treatment of juvenile myelomonocytic leukemia. J Clin Med. 2021. 10.3390/jcm10143084. PubMed DOI PMC

Arber DA, et al. International consensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical and genomic data. Blood. 2022;140(11):1200–28. PubMed DOI PMC

Ordway JM, Williams K, Curran T. Transcription repression in oncogenic transformation: common targets of epigenetic repression in cells transformed by Fos Ras or Dnmt1. Oncogene. 2004;23(21):3737–48. PubMed DOI

Sakaguchi H, et al. Aberrant DNA methylation is associated with a poor outcome in juvenile myelomonocytic leukemia. PLoS ONE. 2015;10(12):e0145394. PubMed DOI PMC

Kitazawa H, et al. Simple and robust methylation test for risk stratification of patients with juvenile myelomonocytic leukemia. Blood Adv. 2021;5(24):5507–18. PubMed DOI PMC