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. 1. Juvenile Myelomonocytic Leukemia (JMML) and Current Clinical Standard of Care Juvenile myelomonocytic leukemia (JMML) is a rare hematologic malignancy of early childhood with high mortality. It represents 2% to 3% of all pediatric leukemias [1, 2], and its incidence is approximately 0.6 per million children per year [3]. Clinically, patients often present with pallor, failure to thrive, decreased appetite, irritability, dry cough, tachypnea, skin rashes, and diarrhea and are found to have lymphadenopathy and hepatosplenomegaly on examination [4–8]. JMML is characterized by leukocytosis with prominent monocytosis, thrombocytopenia, elevation of fetal hemoglobin (HbF), and hypersensitivity of hematopoietic progenitors to granulocyte-macrophage colony-stimulating factor (GM-CSF) [4–8]. Prior to the revision in 2008, JMML was diagnosed based on the following criteria: presence of peripheral blood monocytosis (>1000/μL); less than 20% blasts in the bone marrow; absence of Philadelphia (Ph) chromosome or BCR-ABL fusion gene AND at least two of the following criteria: increased HbF levels; presence of immature myeloid precursors in the peripheral blood; white blood cell count >10,000/μL; GM-CSF hypersensitivity of myeloid progenitors in vitro [5, 9]. In 2008, the JMML diagnostic criteria were revised to account for the molecular genetic abnormalities that were identified in this disease [5]. The natural course of JMML is rapidly fatal with 80% of patients surviving less than three years [10]. Low platelet count, age at diagnosis older than 2 years, and high HbF percentage have been shown to correlate with poor outcome [11]. 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. Patients with Noonan syndrome often develop a JMML-like myeloproliferative disorder that may resolve spontaneously within
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