Role of Hypomethylating Agents in the Treatment of Bone Marrow Failure
Abstract
The central goal of this project is to identify mutations that alter sensitivity to hypomethylating agents. Initial studies indicated that TET2 mutant MDS cells are sensitive to these drugs. In the past year, we have used functional studies, as proposed in Aim 2, to find that cells with cohesin gene mutations are sensitized to hypomethylating agents. We used CRISPR/Cas9genome engineering of primary human hematopoietic stem and progenitor cells (HSPCs), the cells of origin for myeloid malignancies to study and validate this finding. In this model, we first validated that TET2 mutations increased the sensitivity of cells to azacitidine, and ASXL1 mutations decreased sensitivity to azacitidine, recapitulating the human genetic data described in Aim 1A. In addition, we found that cohesin-mutated hematopoietic cells were sensitive to azacitidine treatment. We have validated this finding in cell lines with engineered cohesin gene mutations. The establishment of insulated neighborhoods, keyfunctional elements of chromatin structure, are defined by CTCF-cohesin complexes. Binding of CTCF is highly methylation sensitive. We are therefore examining whether hypomethylating agents alter CTCF binding and disrupt the aberrant insulated neighborhoods found in cohesin-mutated MDS.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2016
- Accession Number
- AD1026506
Entities
People
- Benjamin L. Ebert