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Therapeutic Targeting of Spliceosomal-Mutant Acquired Bone Marrow Failure Disorders

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Technical Report,01 May 2016,30 Apr 2017

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Sloan Kettering Institute for Cancer Research New York United States

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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 targetsevents by mutant SF3B1 and SRSF2 results in hyperactivated NFsub -K 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.

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  • Medicine and Medical Research

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