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<p>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 (<i>BMP4</i>) gene as a single predictor of disease outcomes in a cohort of 111 children diagnosed with JMML, alongside 9 healthy controls. Methylation levels of <i>BMP4</i>, 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 <i>BMP4</i> bs-NGS and genome-wide methylation array data revealed a strong positive correlation (<i>p</i> &lt; 0.001). The sensitivity and specificity of <i>BMP4</i> bs-NGS for classifying high-methylation cases were 0.612 and 0.887, respectively. For <i>PTPN11</i>-mutant patients (<i>N </i>= 40), the sensitivity was 0.667 and the specificity was 0.842. Survival analysis indicated that patients with high <i>BMP4</i> methylation (<i>BMP4</i>h) had lower 5-year disease-free survival (DFS) rates than those with normal <i>BMP4</i> methylation (<i>BMP4</i>n). Specifically, the 20% of patients with highest <i>BMP4</i> methylation had a 5-year DFS of 0.38, in contrast to 0.62 for the lowest 20% (<i>p</i> = 0.007). These findings highlight the potential of <i>BMP4</i> methylation analysis as a complementary biomarker for JMML risk stratification, mirroring genome-wide methylation profiles known to associate with prognostic subgroups.</p>

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Epigenetic risk stratification in juvenile myelomonocytic leukemia by targeted methylation analysis of the BMP4 locus

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月3日

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  • 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

摘要

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.