Research Article: Molecular Targets for the Treatment of Juvenile Myelomonocytic Leukemia

Date Published: November 13, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Xiaoling Liu, Himalee Sabnis, Kevin D. Bunting, Cheng-Kui Qu.


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.

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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].

The molecular defects in JMML result in deregulated signaling through the RAS pathway [15–17]. These mutations are mutually exclusive which highlights the major functional role of the RAS pathway activation in JMML pathophysiology and disease progression. The specific genes implicated in JMML are summarized in Table 1.

Some chromosome abnormalities were found in JMML. The most common chromosome abnormalities in JMML patients are monosomy 7 or deletion 7q (-7/del(7q)) [56]. In addition, there are some case reports for other chromosomal aberrations. For example, a 11-month-old boy with JMML had deletion 5q as the sole clonal chromosome abnormality [57]. Another JMML patient had a chromosomal translocation at t(1;5) [58]. Also, leukemic cells in a JMML patient harbored a 46,XX,der(12)t(3;12) (q21~22;p13.33) karyotype and subsequently developed partial trisomy of 3q [59]. However, at this time specific genes associated with these breakpoints are not yet identified, and; thus, the relevance of these chromosomal aberrations remains to be determined.

The recent focus in JMML has concentrated on using the information gained from knowledge of these molecular defects in order to design targeted drug therapy. Animal models, especially mouse models of the disease, are commonly used to test molecularly targeted agents. Since RAS hyperactivation is very important in the pathophysiology of JMML, agents designed to decrease RAS activity are being evaluated. There are numerous approaches that have been tested to target this pathway (Figure 1).

The clinical therapy of JMML has significantly improved over the last 20 years. However, the low incidence of the disease has limited the capacity to perform large-scale pathophysiological studies and testing newer therapeutic strategies. JMML is a disease that only occurs in children, and drug dosage modifications are needed in children as compared to adults. All these factors limit the development of JMML treatment to some extent. Specific inhibitors for the molecular targets identified in this disease are still lacking.




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