p15INK4b gene methylation and myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are clonal disorders, which frequently undergo leukemia transformation. It was recently shown that the promoter of the p15(INK4b) but not the p16(INK4a) gene is frequently and selectively hypermethylated in MDS, The p15(INK4b) gene is a cyclin dependent kinase inhibitor gene, which is actively transcribed after TGF beta exposure. Methylation of the p15(INK4b) gene is significantly correlated with blastic bone marrow involvement, and sequential analyses have shown that methylation increases with disease evolution toward AML. These data strongly suggest that p15(INK4b) gene methylation is a mechanism allowing leukemic cells to escape to inhibitory signals from the bone marrow environment, however the exact role of p15(INK4b) gene methylation in disruption of the signal mediated by TGF beta remains to be investigated.