Overexpression Of DNMT3a and DNMT3b Is Related To Downregulation Of Mir-29a In Juvenile Myelomonocytic Leukemia (JMML)

Juvenile myelomonocytic leukemia (JMML) is a mixed myelodysplastic /myeloproliferative disorder (MDS/MPD). It occurs in infancy and young children with a progressive course leading to death within one year after diagnosis. This disease is characterized by monocytosis, leukocytosis, elevated fetal hemoglobin, hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), a low percentage of myeloblasts in the bone marrow, and absence of the Philadelphia chromosome or the BCR/ABL fusion gene. Mutations or other abnormalities in RAS, NF1, PTPN11, and CBL have been linked to be responsible for the pathogenesis of JMML in up to 85% of cases. Treatment is very difficult in JMML, and only allogeneic stem cell transplantation (SCT) can extend survival. However, the relapse rate from allogeneic SCT is inordinately high in JMML (28-55%), with 5-year disease-free survival rates of 25-40%. JMML occurs in an age-range when genes are actively being turned on or off in children in adaption to the oxygenized environment after birth. Epigenetics plays a key role in this developmental plasticity. We previously reported hypermethylation on the promoter of PTEN in 77% of JMML patients, and decitabine, a DNA-hypomethylating reagent, significantly inhibited colony formation (CFU-GM) in JMML cells in vitro. In addition, other groups found that aberrant DNA methylation on promoters of BMP4, CALCA, CDKN2B, and RARB is significantly associated with poor prognosis in JMML. Taking together, these data suggest that epigenetic mechanisms may contribute to the pathogenesis of JMML.