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      The spliceosome is a therapeutic vulnerability in MYC-driven cancer


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          c-MYC (MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its pro-tumorigenic functions have been attributed to its ability to regulate gene expression programs 13 . Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts 47 . While such increases in RNA and protein production may endow cancer cells with pro-tumor hallmarks, this elevation in synthesis may also generate new or heightened burden on MYC-driven cancer cells to properly process these macromolecules 8 . Herein, we discover the spliceosome as a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (SF3B1, U2AF1, and others) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total pre-mRNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Importantly, genetic or pharmacologic inhibition of the spliceosome in vivo impairs survival, tumorigenicity, and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.

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          Most cited references23

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          Myc's broad reach.

          The role of the myc gene family in the biology of normal and cancer cells has been intensively studied since the early 1980s. myc genes, responding to diverse external and internal signals, express transcription factors (c-, N-, and L-Myc) that heterodimerize with Max, bind DNA, and modulate expression of a specific set of target genes. Over the last few years, expression profiling, genomic binding studies, and genetic analyses in mammals and Drosophila have led to an expanded view of Myc function. This review is focused on two major aspects of Myc: the nature of the genes and pathways that are targeted by Myc, and the role of Myc in stem cell and cancer biology.
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            Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis.

            The c-myc proto-oncogene product, Myc, is a transcription factor that binds thousands of genomic loci. Recent work suggested that rather than up- and downregulating selected groups of genes, Myc targets all active promoters and enhancers in the genome (a phenomenon termed 'invasion') and acts as a general amplifier of transcription. However, the available data did not readily discriminate between direct and indirect effects of Myc on RNA biogenesis. We addressed this issue with genome-wide chromatin immunoprecipitation and RNA expression profiles during B-cell lymphomagenesis in mice, in cultured B cells and fibroblasts. Consistent with long-standing observations, we detected general increases in total RNA or messenger RNA copies per cell (hereby termed 'amplification') when comparing actively proliferating cells with control quiescent cells: this was true whether cells were stimulated by mitogens (requiring endogenous Myc for a proliferative response) or by deregulated, oncogenic Myc activity. RNA amplification and promoter/enhancer invasion by Myc were separable phenomena that could occur without one another. Moreover, whether or not associated with RNA amplification, Myc drove the differential expression of distinct subsets of target genes. Hence, although having the potential to interact with all active or poised regulatory elements in the genome, Myc does not directly act as a global transcriptional amplifier. Instead, our results indicate that Myc activates and represses transcription of discrete gene sets, leading to changes in cellular state that can in turn feed back on global RNA production and turnover.
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              Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole genome sequencing to perform an unbiased comprehensive screen to discover all the somatic mutations in a sAML sample and genotyped these loci in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (S34) in U2AF1 was recurrently mutated in 13/150 (8.7%) de novo MDS patients, with suggestive evidence of an associated increased risk of progression to sAML. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3′ end of introns and mutations are located in highly conserved zinc fingers in U2AF1 1,2 . Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This novel, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis.

                Author and article information

                25 March 2016
                02 September 2015
                17 September 2015
                14 April 2016
                : 525
                : 7569
                : 384-388
                [1 ]Verna & Marrs McLean Dept. of Biochemistry and Molecular Biology
                [2 ]Interdepartmental Program in Molecular and Biomedical Sciences
                [3 ]Medical Scientist Training Program
                [4 ]Dept. of Molecular and Human Genetics
                [5 ]The Lester and Sue Smith Breast Center
                [6 ]Dept. of Molecular Physiology and Biophysics
                [7 ]Dept. of Pediatrics
                [8 ]Dept. of Pathology and Immunology
                [9 ]Dept. of Molecular and Cellular Biology Baylor College of Medicine, Houston, TX 77030, USA
                [10 ]Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
                [11 ]Department of Medical Biophysics, University of Toronto, Canada
                [13 ]Center for Chemical Biology, Bioscience Division, SRI International, Menlo Park, CA 94025, USA
                [14 ]Department of Physics, University of Illinois, Urbana, IL 61801, USA
                Author notes
                [# ]Correspondence and requests for materials should be addressed to T.F.W. ( thomasw@ 123456bcm.edu )

                present address: Humacyte, Morrisville, NC 27560, USA


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