JMML is an aggressive mixed myeloproliferative/myelodysplastic neoplasm that occurs mainly in young children. Although allogeneic hematopoietic stem cell transplantation (HSCT) is still the mainstay of successful therapy, it is associated with considerable toxicity and a high risk of failure. Accordingly, we aim to understand the mechanisms regulating treatment resistance and relapse of the disease.
Our previous studies have confirmed the involvement of epigenetic mechanisms in the etiopathogenesis of JMML. The most common epigenetic alteration involves cytosine hypermethylation at 5‘ genetic regions, already considered a hallmark of high-risk JMML. Therefore, the characterization of disordered global and focal DNA methylation and its consequences will contribute to better diagnosis and management of JMML.
Specifically, we use our established xenograft model to functionally analyse the clonal epigenetic architecture and intra-patient diversity in JMML patients, along with its changes before and after treatment with DNA methyltransferase inhibitors such as azacitidine. Furthermore, we aim to integrate genome-wide DNA methylation profiles and alterations in the transcriptome and proteome. The efficacy of azacitidine for treatment of JMML was demonstrated and confirmed in a multicenter, international, phase 2 clinical trial (AZA-JMML 001, registered as a Pediatric Investigation Plan with the European Medicines Agency), for which our institution provided central medical coordination, reference diagnostics, and pharmacodynamic studies. In an ancillary study to this trial, we focus on understanding the early cellular effects of DNA hypomethylation in JMML by integrated DNA methylation profiling, transcriptome analysis, and mass-spectrometry proteomics.