Abstract
Significant advances in our understanding of the genetic defects and the pathogenesis of juvenile myelomonocytic leukemia (JMML) have been achieved in the last several years. The information gathered tremendously helps us in designing molecular targeted therapies for this otherwise fatal disease. Various approaches are being investigated to target defective pathways/molecules in this disease. However, effective therapy is still lacking. Development of specific target-based drugs for JMML remains a big challenge and represents a promising direction in this field.
Highlights
The natural course of juvenile myelomonocytic leukemia (JMML) is rapidly fatal with 80% of patients surviving less than three years [10]
Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for JMML, but controversy exists in identifying the patients that need to proceed to transplant immediately versus those that can be observed for a longer time
De Filippi et al reported a 38G > A (G13D) mutation in the NRAS gene in all types of cells checked in a male infant who was diagnosed with JMML [41]
Summary
The molecular defects in JMML result in deregulated signaling through the RAS pathway [15,16,17]. PTPN11 mutations found in JMML are mainly localized in the NSH2 domain These mutations result in amino acid changes at the interface formed between N-SH2 and PTP domains, disrupting the inhibitory intramolecular interaction, leading to hyperactivation of SHP-2 catalytic activity [18, 31]. De Filippi et al reported a 38G > A (G13D) mutation in the NRAS gene in all types of cells checked in a male infant who was diagnosed with JMML [41]. This case suggests that constitutively active mutations of NRAS may be responsible for the development of JMML in children [41].
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