Epigenetics of MDS

University Of Tx Md Anderson Can Ctr, Houston TX

Investigators

Linked publications & trials

Abstract

Epigenetic changes marked by promoter DMA methylation and histone modifications are recognized mediators of gene silencing that likely play critical roles in neoplastic transformation and progression. In the myelodysplastic syndromes (MDS), DNA methylation has been postulated to play a role in progression, and inhibitors of DNA methylation (decitabine and azacytidine) are among the most clinically active single agents in this disease. However, we lack a global picture of DNA methylation changes in MDS, it remains unclear whether subsets of patients benefit preferentially from DNA methylation inhibitors, and it is not known whether demethylation of critical genes mediates responses to these agents. In this project, we will combine basic science and clinical expertise at MD Anderson (MDACC) to address the following hypotheses: (i) DNA methylation abnormalities mark a subset of patients with MDS that are more likely to progress to AML; (ii) Patients with specific patterns of methylation are more likely to respond to DNA methylation inhibitors, and (iii) global and gene-specific demethylation mediates responses to DNA methylation inhibition in MDS. These hypotheses will be tested using the following specific aims; (a) Clone a panel of CpG islands hypermethylated in MDS and use these as well as established markers to profile DNA methylation in consecutive MDS cases; (b) Profile DNA methylation patterns at baseline in all patients entered on decitabine trials at MDACC and correlate the profiles with likelihood to respond to therapy, and (c) Study global and gene-specific methylation as well as gene expression (for selected genes) before, during and after decitabine therapy and correlate these with responses to the agent. Overall, this project aims at clarifying the role of epigenetic changes and their manipulation in MDS, and to rapidly translate these findings to the clinical care of patients with this disease.