P15INK4bGene Methylation and Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are clonal disorders, which frequently undergo leukemic transformation. It was recently shown that the promoter of the p15INK4b but not the p16INK4a gene is frequently and selectively hypermethylated in MDS. The p15INK4b gene is a cyclin dependent kinase inhibitor gene, which is actively transcribed after TGFbeta exposure. Methylation of the p15INK4b 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 p15INK4b gene methylation is a mechanism allowing leukemic cells to escape to inhibitory signals from the bone marrow environment, however the exact role of p15INK4b gene methylation in disruption of the signal mediated by TGFbeta remains to be investigated.