The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

Larráyoz, Marta; Blakemore, Stuart; Dobson, Rachel; Blunt, Matthew D.; Rose-Zerilli, Matthew; Walewska, Renata; Duncombe, Andrew; Oscier, David; Koide, Kazunori; Forconi, Francesco; Packham, Graham; Yoshida, Minoru; Cragg, Mark S.; Strefford, Jonathan C.; Steele, Andrew J.

doi:10.1038/leu.2015.286

Cited by 89 publications

(73 citation statements)

References 59 publications

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“…Additionally, inhibition of SF3B1 by spliceostatin-A was toxic to CLL independent of SF3B1 mutational status, suggesting a broader role for aberrant splicing in CLL biology (66). The observation of broadly consistent overexpression of spliceosomal proteins (Figure 7), may therefore offer some explanation for these previous observations.…”

Section: Discussionmentioning

confidence: 52%

Proteomics Profiling of CLL Versus Healthy B-cells Identifies Putative Therapeutic Targets and a Subtype-independent Signature of Spliceosome Dysregulation

Johnston

Carter

Larráyoz

et al. 2018

Molecular & Cellular Proteomics

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Section: Discussionmentioning

confidence: 52%

Proteomics Profiling of CLL Versus Healthy B-cells Identifies Putative Therapeutic Targets and a Subtype-independent Signature of Spliceosome Dysregulation

Johnston

Carter

Larráyoz

et al. 2018

Molecular & Cellular Proteomics

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“…In vitro exposure of primary CLL cells to FD-895 (50), pladienolide B (50), or spliceostatin A (51) results in increased apoptosis of CLL cells compared with normal B-cells, regardless of SF3B1 mutational status. However attempts to study the efficacy of these compounds in vivo in the context of CLL have largely been limited by the lack of stable and robust PDX models of CLL (52) as well as genetically engineered CLL models with Sf3b1 mutations .…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Understanding and Targeting Mutant Spliceosomal Proteins

Yoshimi

Abdel‐Wahab

2017

Clinical Cancer Research

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Splicing of precursor messenger RNA is a critical step in regulating gene expression and major advances are being made in understanding the composition and structure of the enzymatic complex which performs splicing, termed the spliceosome. In parallel, there has been increased appreciation for diverse mechanisms by which alterations in splicing contribute to cancer pathogenesis. Key among these includes change-of-function mutations in genes encoding spliceosomal proteins. Such mutations are amongst the most common genetic alterations in myeloid and lymphoid leukemias, making efforts to therapeutically target cells bearing these mutations critical. To this end, recent studies have clarified that pharmacologic modulation of splicing may be preferentially lethal for cells bearing spliceosomal mutations and also may have role in the therapy of MYC-driven cancers. This has culminated in the initiation of a clinical trial of a novel oral spliceosome modulatory compound targeting the SF3B complex and several novel alternative approaches to target splicing are in development as reviewed here. There is therefore now a great need to understand the mechanistic basis of altered spliceosomal function in cancers and to study the effects of spliceosomal modulatory compounds in pre-clinical settings and in well-designed clinical trials.

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“…78 In CLL cells, SSA potently depletes MCL-1 via alternative splicing, leading to induction of apoptosis at low nanomolar concentrations in vitro, with relative sparing of normal T and B cells. 79 Pladienolide B (PB), FD-895, and herboxidiene are natural products of Streptomyces sp. that share a common pharmacophore with FR.…”

Section: Splicing Modulatorsmentioning

confidence: 99%

Splicing factor gene mutations in hematologic malignancies

Sáez

Walter

Graubert

2017

Blood

112

108

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Alternative splicing generates a diversity of messenger RNA (mRNA) transcripts from a single mRNA precursor and contributes to the complexity of our proteome. Splicing is perturbed by a variety of mechanisms in cancer. Recurrent mutations in splicing factors have emerged as a hallmark of several hematologic malignancies. Splicing factor mutations tend to occur in the founding clone of myeloid cancers, and these mutations have recently been identified in blood cells from normal, healthy elderly individuals with clonal hematopoiesis who are at increased risk of subsequently developing a hematopoietic malignancy, suggesting that these mutations contribute to disease initiation. Splicing factor mutations change the pattern of splicing in primary patient and mouse hematopoietic cells and alter hematopoietic differentiation and maturation in animal models. Recent developments in this field are reviewed here, with an emphasis on the clinical consequences of splicing factor mutations, mechanistic insights from animal models, and implications for development of novel therapies targeting the precursor mRNA splicing pathway. (Blood. 2017;129(10):1260-1269 IntroductionThe control of messenger RNA (mRNA) processing is a crucial component of gene regulation. The precursor messenger RNA (premRNA) sequence contains exons that flank introns, which are removed during splicing.1 Human genes are remarkably complex, containing an average of 8 exons, with introns composing up to 90% of the pre-mRNA sequence.2,3 Up to 94% of human genes generate multiple mRNA isoforms. [4][5][6] The spliceosome is a multiprotein complex consisting of 5 small nuclear ribonucleoproteins (snRNPs) and more than 150 proteins that recognizes the elements near intron-exon boundaries and the branch site that catalyzes the excision of intronic regions. Additional trans-acting factors including SR proteins bind the cis-regulatory sequences (exonic and intronic silencers and enhancers) to promote or prevent spliceosome assembly. [7][8][9] The complexity of regulatory elements that control proper splicing makes this process not only critical to maintain tissue homeostasis, but also highly susceptible to hereditary and somatic mutations that are involved in disease. This review will discuss the implications of aberrant splicing on human disease, with a focus on the impact of somatic mutations in trans-acting splicing factors in hematologic malignancies. Splicing and diseaseA comprehensive analysis of The Cancer Genome Atlas (TCGA) project RNA sequencing (RNA-seq) data from 16 tumor types and matched normal tissue revealed evidence of global alternative splicing involving a variety of splicing junctions, including cassette exons, retrained introns, and competing 59 and 39 splice sites (SSs). 10 In particular, acute myeloid leukemia (AML) cells showed the largest number of alternative spliced events among tumor types.10 Recent evidence from analysis of paired DNA and RNA-seq data from TCGA has shown that somatic mutations affecting splicing regulatory sequences (sp...

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The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

Cited by 89 publications

References 59 publications

Proteomics Profiling of CLL Versus Healthy B-cells Identifies Putative Therapeutic Targets and a Subtype-independent Signature of Spliceosome Dysregulation

Proteomics Profiling of CLL Versus Healthy B-cells Identifies Putative Therapeutic Targets and a Subtype-independent Signature of Spliceosome Dysregulation

Molecular Pathways: Understanding and Targeting Mutant Spliceosomal Proteins

Splicing factor gene mutations in hematologic malignancies

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