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Gene-Specific Demethylation as Targeted Therapy in MDS
Technical Report,15 Jun 2015,14 Jun 2016
Beth Israel Deaconess Medical Center, Boston Boston United States
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Myelodysplastic Syndromes MDS are a group of clonal hematopoietic disorders characterized by bone marrow failure and risk of progression to Acute Myeloid Leukemia AML in approximately 30 percent of the cases. Aberrant DNA methylation is considered a dominant mechanism for Tumor Suppressor Genes silencing during MDS evolution to AML, but the causes leading to aberrant DNA methylation remain elusive. This proposal builds on our recent discovery of a novel class of RNAs, the DiRs or DNMT1-interacting RNAs, involved in cell type-specific DNA methylation patterns. Based on these findings, we hypothesize that DNA methylation changes can be corrected by RNAs. We aim to demonstrate that a by inducing transcription within targeted methylated genomic loci or b by utilizing oligonucleotides mimicking the function of DiRs and able to specifically target methylated loci, we will be able to reduce level of methylation and consequently rescue the expression of the respective silent gene. In this proposal we plan to apply these approaches to yet another gene, P15 CDKN2B, the gene most frequently silenced by aberrant promoter methylation in MDS and it is associated with poor prognosis and increased risk of transformation to AML. Therefore, we propose the following two aims Aim 1. To reduce P15 locus specific genomic methylation by induction of its respective DiR Aim 2. To reduce P15 locus specific DNA methylation by introduction of oligonucleotides mimicking the action of the P15-DiR.
APPROVED FOR PUBLIC RELEASE