JMML

 

Juvenile myelomonocytic leukemia (JMML) is a complex and rare pediatric cancer with a markedly aggressive clinical course. Despite identification of five genetic subtypes (NRAS, KRAS, PTPN11, CBL and NF1) and several secondary mutations, our current understanding falls short in fully capturing the phenotypic and prognostic heterogeneity observed among patients. Current research is exploring epigenomics and transcriptomics to understand gene activity. Notably, DNA methylation has emerged as the current most reliable predictor of clinical outcome in JMML.

A second type of epigenetic regulation, namely non-coding RNAs, has also received attention the past years, revealing dysregulation of microRNAs (miRNA), long non-coding RNAs (lncRNA) and circular RNAs (circRNA) in JMML. Our team has taken on a leading role in these efforts, establishing a comprehensive profiling of the lncRNA landscape in JMML patients. Currently, the lab is evaluating the therapeutic potential of these findings in vivo. The lab also performed a comprehensive circRNA profiling in JMML patients, identifying a unique circRNA expression landscape. Interestingly, distinct circRNA expression signatures show associations with the five genetic subgroups. Moreover, predicted interactions with miRNAs link several dysregulated circRNAs, including highly upregulated circMCTP1, to regulatory networks. These insights not only deepen our understanding of JMML pathobiology but have also set the stage for further functional investigations undertaken by the our team.

A third essential epigenetic mechanism is that of histone post-translational modifications (hPTMs). Currently we are dedicating our efforts to reveal the various dynamic post-translational modifications (PTMs) that make up the “histone code” of JMML patients. Expanding our investigative scope, the team is also venturing into proteomics, which offers a complementary dimension to cancer research. Proteomics studies hold the promise of identifying dysregulations undetectable through genomic or transcriptomic approaches alone. As our grasp of protein expression and its implications in cancer advances, so does the potential for innovative therapeutic interventions.

Ultimately the goal is to acquire a full integration of clinical, genomic, epigenomic, transcriptomic and proteomic data of JMML patients. Such a comprehensive multi-omics approach will allow refinement of JMML subtypes based on the underlying biological mechanisms and clinical outcomes. This finer-scale subtyping is part of a growing trend in cancer research towards personalized medicine. Ultimately, a deeper understanding of JMML pathobiology will enhance our ability to accurately predict its clinical course and tailor advanced treatment strategies.

Latest Publication

De Vos N, Hofmans M, Lammens T, De Wilde B, Van Roy N and De Moerloose B. (2022). Targeted therapy in juvenile myelomonocytic leukemia: Where are we now? Ped. Blood Cancer 69(11): e29930. DOI: 10.1002/pbc29930. PMID: 36094370