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Understanding and Targeting Mutant Spliceosomal Proteins Akihide Yoshimi1 and Omar Abdel-Wahab1,2

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Understanding and Targeting Mutant Spliceosomal Proteins Akihide Yoshimi1 and Omar Abdel-Wahab1,2 Published OnlineFirst November 10, 2016; DOI: 10.1158/1078-0432.CCR-16-0131 Molecular Pathways Clinical Cancer Research Molecular Pathways: Understanding and Targeting Mutant Spliceosomal Proteins Akihide Yoshimi1 and Omar Abdel-Wahab1,2 Abstract Splicing of precursor messenger RNA is a critical step in regu- recent studies have clarified that pharmacologic modulation of lating gene expression, and major advances are being made in splicing may be preferentially lethal for cells bearing spliceosomal understanding the composition and structure of the enzymatic mutations and may also have a role in the therapy of MYC-driven complex that performs splicing, which is termed the "spliceo- cancers. This has culminated in the initiation of a clinical trial of a some." In parallel, there has been increased appreciation for novel oral spliceosome modulatory compound targeting the SF3B diverse mechanisms by which alterations in splicing contribute complex, and several novel alternative approaches to target splic- to cancer pathogenesis. Key among these include change-of- ing are in development as reviewed here. There is now, therefore, a function mutations in genes encoding spliceosomal proteins. great need to understand the mechanistic basis of altered spli- Such mutations are among the most common genetic alterations ceosomal function in cancers and to study the effects of spliceo- in myeloid and lymphoid leukemias, making efforts to therapeu- somal modulatory compounds in preclinical settings and in well- tically target cells bearing these mutations critical. To this end, designed clinical trials. Clin Cancer Res; 23(2); 336–41. Ó2016 AACR. Background mRNAforsplicingofthecorrectsegmentsofRNA(Fig.1B–D). Here, we present a simplified summary of the spliceosome Basic mechanisms of precursor messenger RNA splicing assembly pathway and the factors required for exon definition Aberrant regulation of gene expression is a well-known (Fig. 1B). hallmark of cancer cells. As such, mRNA splicing, the 0 An intron is defined by four consensus elements: (i) the 5 process of removing introns from precursor messenger RNA 0 0 0 splicesite(5 SS; located at the 5 end of the intron), (ii) the 3 (pre-mRNA), represents a critical step in the posttranscriptional 0 SS (located at the 3 end of the intron), (iii) the branch regulation of gene expression. More than 95% of human genes 0 point sequence (BPS; located upstream of the 3 SS), and (iv) are capable of generating multiple RNA species through alter- the polypyrimidine tract (located between the BPS and the native splicing, and this process enables cells to generate a 0 3 SS; Fig. 1C). These sequences are critical in allowing the diversity of functionally distinct proteins from a single gene. spliceosome to recognize nucleotide sequences as introns and mRNA splicing is carried out inside the nucleus by an enzy- to distinguish introns from exonic sequence. For the majority of matic complex known as the spliceosome. The spliceosome is a 0 introns, the 5 SS is characterized by a GU dinucleotide, whereas metalloribozyme that consists of five small nuclear ribonu- 0 the 3 SS contains an AG dinucleotide. These 2 sequences are cleoproteins (snRNP; U1, U2, U4, U5, and U6 snRNPs), each of not sufficient by themselves to define an intron in most cases, which contains its own small nuclear RNA (snRNA) complexed and a variable stretch of pyrimidine nucleotides, called the to a group of proteins and more than 200 related proteins. 0 polypyrimidine tract, further helps define the 3 SS. The poly- Recent utilization of cryoelectron microscopy has enabled 0 pyrimidine tract is situated between the 3 SS and the BPS, and an unprecedented high-resolution view of each step in splicing 0 also serves to recruit splicing factors to the 3 SS and BPS. The (1–5). Although splicing is a complex multistep process BPS, so named as it consists of a nucleotide that initiates a (reviewed in refs. 6–10 in detail), the crux of splicing cataly- 0 nucleophilic attack on the 5 SS to create a branch-like structure, sis consists of two sequential transesterification reactions contains a conserved adenosine nucleotide required for the first (Fig. 1A). Base pairing of snRNAs to conserved sequences on step of splicing (Fig. 1A). pre-mRNA as well as interactions of numerous splicing acces- The early steps of spliceosome assembly are then achieved by sory proteins and RNA–protein interactions are essential in 0 binding of the 5 SS and BPS by the U1 and U2 snRNPs, respec- guiding the massive spliceosomal complex to regions of pre- tively, through base-pairing interactions. The U2 snRNP consists of SF3A, SF3B, and a 12S RNA subunit in which SF3B1 is involved 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer in the binding to the BPS. The likelihood of splicing at a particular Center and Weill Cornell Medical College, New York, New York. 2Leukemia site is influenced by additional proteins outside of the core Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New spliceosome. For example, members of the serine/arginine (SR) York, New York. family of proteins generally promote splicing by recognizing Corresponding Author: Omar Abdel-Wahab, Memorial Sloan Kettering Cancer specific sequences in pre-mRNA, named exonic and intronic Center, Zuckerman Research Building, 415 East 68th Street, New York, NY splicing enhancers (ESE and ISE; Fig. 1D). SR proteins generally 10065. Phone: 347-821-1769; Fax: 646-422-0856; E-mail: [email protected] act as enhancers of splicing from nearby splice sites by interacting doi: 10.1158/1078-0432.CCR-16-0131 with these sequences and recruiting the U1 snRNP and U2AF to 0 0 Ó2016 American Association for Cancer Research. 5 SS and 3 SS, respectively. In contrast, heterogeneous nuclear 336 Clin Cancer Res; 23(2) January 15, 2017 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst November 10, 2016; DOI: 10.1158/1078-0432.CCR-16-0131 Understanding and Targeting Mutant Spliceosomal Proteins ribonucleoproteins (hnRNP) generally suppress splicing by inter- Clinical–Translational Advances acting with exonic and intronic splicing silencers (ESS and ISS). As mentioned above, recent studies have suggested that spli- Altered mRNA splicing in cancer ceosomal-mutant malignancies are preferentially sensitive to Growing evidence has revealed that mis-splicing of pre-mRNA pharmacologic or genetic modulation of splicing compared with – can promote cancer initiation, maintenance, and/or progression. spliceosomal wild-type cancers or normal cells. To this end, Genetic alterations in cancer that contribute to mis-splicing fall natural products from several bacteria species and their analogs into two categories: (i) mutations falling within the mRNA have been discovered that bind SF3B1 (and possibly other com- sequence that is being spliced and thereby influencing splicing ponents of U2 snRNP) and block early spliceosome assembly. (so-called "cis-acting" mutations) and (ii) alterations in the level These compounds, which include E7107 (an analogue of pladi- of expression or mutations in splicing factors that promote enolide B; ref. 40), spliceostatin A (41), and the sudemycins (42), splicing of pre-mRNA (so-called "trans-acting" splicing factors). are thought to inhibit the exposure and binding of the branch – Cis-acting mutations include those affecting the 50 SS, 30 SS, point binding region of U2 snRNP to the BPS, thereby blocking BPS, or splicing enhancer or silencer elements. Mutations with the essential conformational change in the U2 snRNP required – pathologic effects on splicing may, therefore, occur within introns for the transition from complex A to complex E (34, 43 45; the or exons and include synonymous as well as nonsynonymous activities and properties of these compounds have been reviewed mutations. Such mutations represent common mechanisms of recently in detail in ref. 46). Although the downstream changes in inactivation of tumor suppressor genes (11). For example, recur- the transcriptome and protein expression caused by these drugs rent synonymous mutations within TP53 occur adjacent to splice are still largely unknown, results from preclinical evaluation of sites, resulting in intron retention or activation of a cryptic splice these compounds in genetic subsets of cancer are promising. in vivo site to produce a frameshifted mRNA subjected to nonsense We recently demonstrated that treatment with E7107 mediated decay (12). Similarly, recurrent somatic mutations in increases retention of both constitutive and alternative introns APC result in exon skipping (13) or creation of a new splice site as well as cassette exon skipping, consistent with E7107 inhibiting (14) in colon and lung cancer, respectively. splicing catalysis. However, the magnitude of splicing inhibition In 2011, recurrent somatic mutations affecting trans-acting following E7107 treatment was more severe in myeloid leukemias Srsf2 spliceosome components were reported in hematopoietic malig- with -mutant versus wild-type leukemias, resulting in nancies (15, 16) and are currently among the most common class decreased disease burden in both isogenic murine leukemia of mutations in patients with myelodysplastic syndromes (MDS; models and acute myeloid leukemia (AML) patient-derived SRSF2 ref. 15) and chronic lymphocytic leukemia (CLL; ref. 17). These xenograft (PDX) models with or without mutations Sf3b1 mutations occur predominantly in both SF3B1
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