Therapeutic Targeting of Spliceosomal-Mutant Acquired Bone Marrow Failure Disorders
Abstract
Genes encoding core components of the RNA splicing machinery are the most common mutational targets in acquired bone marrow failure (BMF) due to myelodysplastic syndromes (MDS). The goals of this proposal were to identify (1) the subset of biologically and therapeutically relevant targets that link spliceosomal mutations to MDS and (2) therapeutic strategies that interfere with the altered function of mutant spliceosomal proteins. Since award of this grant we have found that different spliceosomal mutations, despite imparting distinct effects on splicing and gene expression, are negatively selected for when co-expressed in the same cell or in a homozygous state. At the same time, aberrant splicing of distinct targets/events by mutant SF3B1 and SRSF2 results in hyperactivated NF-kB signaling, thereby identifying convergent biological consequences of splicing factor mutations and the basis for their mutual exclusivity and heterozygous nature. In addition, we have completed both a negative selection shRNA screen and a genome-wide CRISPR dropout screen to identify genes selectively required in spliceosomal mutant cells. This effort has also highlighted a requirement for innate immune signaling in SF3B1-mutant MDS and has implicated a few specific proteins as potential novel therapeutic targets for spliceosomal mutant MDS.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2018
- Accession Number
- AD1063019
Entities
People
- Omar Abdel-Wahab
Organizations
- Sloan-Kettering Institute