**Conflict of interest**

*Acute Leukemias*

is not completely explained by the clinical and genetic markers which lent the epigenetic landscape of JMML a particular interest. There is hardly any pediatric oncology entity where research has benefited as much from epigenetics as JMML. Genome-wide interrogation of DNA methylation patterns has led to a classification of the disease into three distinct JMML subgroups that have clear pathogenetic and prognostic relationships. The DNA hypermethylation signature is associated with poor clinical outcome and increased risk for relapse following HSCT. Evidence suggests that DNA methylation changes could be used as a potential biomarker in a combined risk stratification algorithm in future clinical trials. Although the clinical activity of azacitidine as a DNA hypomethylating agent appears to be promising, it is unlikely that azacitidine alone have the potential to cure JMML [29]. However, azacitidine as monotherapy is safe and effective in controlling disease both in upfront and relapsed patients in order to proceed to HSCT [30]. In fact, azacitidine

Despite the lack of associated mutations in the genes coding for the GMR, JMML is characterized by aberrant GMR signal transduction. This aberrant signaling is integral in the pathogenesis of JMML that underlines the dysregulated myelopoiesis of the disease. The resultant selective GM-CSF hypersensitivity was exploited as a diagnostic tool for JMML and it is especially useful for those diagnostically challenging cases with RAS pathway mutation-negative JMML. This entity represents the remaining 10% of cases where disease might be due to chromosomal translocations, other gene mutations, specific microRNAs (miRNA) or long noncoding RNAs (lncRNAs) [31]. GMR signal transduction is located upstream to both RAS signaling pathway and the JAK/STAT pathway. STAT5 is recruited to phosphorylated tyrosine residues on the activated β subunit of the GM-CSF receptor, indicating that STAT5 signaling profile reflects JMML hypersensitivity to GM-CSF. The p-STAT5 phospho-specific flowcytometry assay which largely replaced the traditional colony assay had also recently gained promising utility in monitoring the disease status. As disease worsens, a greater percentage of cells get hyper-responsive. Therefore, p-STAT5 phospho-flow signature could prove enticing as a marker of disease progression and indicator of relapse. As JMML lacks tractable markers, both DNA methylation and p-STAT5 phospho-flow signature are potential new armamentarium that could serve as futuristic checkpoints in order to promulgate uniform protocols designed to follow patients on therapy. Interestingly, the shared p-STAT5 phospho-flow signature in JMML, AML M4/M5 and CMML could explain

So far HSCT represents the only therapy with a clear impact on the outcome of JMML patients. However, HSCT is replete with significant morbidities and deleterious late effects in this young population. The search for more effective and less toxic strategies coincided with advances in molecular oncology that opened up a realm of novel and targeted molecules capable of improving therapeutic tactics in JMML. In particular, scoping into the genetic basis of hyper-responsiveness in JMML could provide a means of assessing the efficacy of emerging kinase inhibitors such as those blocking the RAS (e.g., the oral MEK inhibitor trametinib) or JAK2-signaling pathways for the treatment of this disease. Notably, a combination of drugs targeting two different pathways might be more effective than a single drug. However, the choice of drugs used for treatment should be entirely based on patient's mutation

I would like to express my deep gratitude for the following:

is currently the gold standard bridge to HSCT in JMML.

the unique overlap of their clinical features.

**30**

status [32, 33].

**Acknowledgements**

The author declares no competing financial interests.
