DMA methylation and associated epigenetic changes lead to functional alterations in pathways that promoteneoplastic development. Therapy targeting DMA methylation and histone deacetylation, another epigeneticmodification, has shown activity in myeloid leukemias, and is now part of standard of care in patients withmyelodysplastic syndrome (MDS). We have identified a DMA hypermethylation signature that characterizesyoung patients with acute myeloid leukemia (AML) who have a high cure rate following standard cytotoxicchemotherapy. This signature was independent of known prognostic factors and, if validated, would providean important tool towards personalized therapy in AML. Separately and paradoxically, we have shown thatprogression in AML (diagnosis to relapse) and in MDS (MDS to AML) is also associated with the progressiveacquisition of aberrant DNA methylation that, in this situation, predicts for a poor overall outcome. Finally, inproof-of-concept studies, we have shown that treatment with the DNA methylation inhibitor DAC results intumor-suppressor gene demethylation and reactivation in AML and MDS, associated with a relatively highresponse rate that correlates with induction of gene expression of the P15 tumor-suppressor. Based onthese observations, we hypothesize that DNA methylation profiling identifies a subset of young patients withAML who are curable with standard chemotherapy. We further hypothesize that DNA methylation, throughseparate genes, also contributes to clonal evolution in AML, leading to relapses with drug resistantphenotypes, and that DNA methylation inhibition in remission will delay or eliminate clonal evolution anddisease relapse in some patients. Finally, we hypothesize that strategies aimed at enhancing pharmacologicepigenetic reactivation will translate into better therapies for myeloid malignancies. To test these hypotheses,we propose the following specific aims: (1) Retrospectively and prospectively validate and extend anepigenetic signature of curability in AML. (2) Conduct a randomized clinical trial of remission maintenance inAML using DAC. (3) Use a methylated and silenced GFP reporter gene selectable system to identify keypathways and pharmacologic combinations that lead to epigenetic reactivation in neoplastic cells. Thisproject will provide new markers of prognosis in AML and new approaches to therapy that are based onincorporating epigenetic modulation into the standard of care of this disease.Lay abstract: DNA methylation is a tag attached to DNA that modifies gene function by preventing RNAformation. Decitabine, a drug that modifies DNA methylation is useful in leukemia. We propose to verify thatDNA methylation can identify patients who are curable with chemotherapy. We also propose to usedecitabine to prevent relapse in AML, and we will find drugs that boost the activity of decitabine and that canbe introduced into clinical trials
Showing the most recent 10 out of 487 publications
