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Proteomics Profiling of CLL Versus Healthy B-Cells Identifies Putative Therapeutic Targets and a Subtype-Independent Signature of Spliceosome Dysregulation*□S

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Proteomics Profiling of CLL Versus Healthy B-Cells Identifies Putative Therapeutic Targets and a Subtype-Independent Signature of Spliceosome Dysregulation*□S los Research © 2018 by The American Society for Biochemistry and Molecular Biology, Inc. This paper is available on line at http://www.mcponline.org Proteomics Profiling of CLL Versus Healthy B-cells Identifies Putative Therapeutic Targets and a Subtype-independent Signature of Spliceosome Dysregulation*□S Harvey E. Johnston‡§, Matthew J. Carter‡, Marta Larrayoz¶, James Clarkeʈ, Spiro D. Garbis§**, David Oscier‡‡, Jonathan C. Strefford¶, Andrew J. Steele§§, Renata Walewska¶¶, and Mark S. Cragg‡ʈʈ Chronic lymphocytic leukemia (CLL) is a heterogeneous esis. Several other proteins (e.g. Wee1, HMOX1/2, HDAC7 Downloaded from B-cell cancer exhibiting a wide spectrum of disease and INPP5F) were identified with significant overexpres- courses and treatment responses. Molecular character- sion that also represent potential targets. Western blot- ization of RNA and DNA from CLL cases has led to the ting confirmed overexpression of a selection of these identification of important driver mutations and disease proteins in an independent cohort. mRNA processing subtypes, but the precise mechanisms of disease pro- machinery were broadly upregulated across the CLL gression remain elusive. To further our understanding of samples. Spliceosome components demonstrated con- http://www.mcponline.org/ ؋ 10؊21) suggesting 1.3 ؍ CLL biology we performed isobaric labeling and mass sistent overexpression (p spectrometry proteomics on 14 CLL samples, comparing dysregulation in CLL, independent of SF3B1 mutations. them with B-cells from healthy donors (HDB). Of 8694 This study highlights the potential of proteomics in the identified proteins, ϳ6000 were relatively quantitated be- identification of putative CLL therapeutic targets and tween all samples (q<0.01). A clear CLL signature, inde- reveals a subtype-independent protein expression sig- pendent of subtype, of 544 significantly overexpressed nature in CLL. Molecular & Cellular Proteomics 17: proteins relative to HDB was identified, highlighting es- 10.1074/mcp.RA117.000539, 776–791, 2018. tablished hallmarks of CLL (e.g. CD5, BCL2, ROR1 and by guest on September 20, 2018 CD23 overexpression). Previously unrecognized surface markers demonstrated overexpression (e.g. CKAP4, 1 PIGR, TMCC3 and CD75) and three of these (LAX1, Chronic lymphocytic leukemia (CLL) , the most common ϩ CLEC17A and ATP2B4) were implicated in B-cell receptor adult leukemia in the western world, is a CD5 B-cell neo- signaling, which plays an important role in CLL pathogen- plasm with a heterogeneous clinical course (1, 2). B-cell re- ceptor (BCR) signaling plays a role in the pathogenesis of CLL, and drugs targeting this pathway are revolutionizing CLL From the ‡Antibody and Vaccine Group, Cancer Sciences Unit, treatment (3). Indeed, the mutational status of the immuno- Faculty of Medicine, General Hospital, University of Southampton, globulin heavy-chain variable-region gene (IGHV) within the Southampton, UK; §Centre for Proteomic Research, Institute for Life Sciences, University of Southampton, Highfield Campus, Southamp- BCR largely correlates with disease outcome. CLL cases with ton, UK; ¶Cancer Genomics, Cancer Sciences Unit, Faculty of Med- unmutated V-genes (U-CLL) typically have a progressive dis- icine, University of Southampton, Southampton, UK.; ʈCancer ease with patients often requiring early treatment, in contrast Sciences Unit, Faculty of Medicine, University of Southampton, cases with mutated V-genes (M-CLL) are more indolent, and Southampton, UK; **Clinical and Experimental Sciences Unit, Faculty those presenting with a low tumor burden often never require of Medicine, University of Southampton, Southampton, UK; ‡‡De- partment of Molecular Pathology, Royal Bournemouth Hospital, Bour- treatment (4). nemouth, UK; §§Leukemia and Lymphoma Molecular Mechanisms CLL transcriptomics analyses have identified minimal dif- and Therapy Group, Cancer Sciences Unit, Faculty of Medicine, ferences in gene expression between subtypes such as U- University of Southampton, Southampton, UK; ¶¶Department of and M-CLL suggesting that common mechanisms elicit CLL Haematology, Royal Bournemouth Hospital, Bournemouth, UK Received December 14, 2017 Published, MCP Papers in Press, January 24, 2018, DOI 10.1074/ 1 The abbreviations used are: CLL, Chronic lymphocytic leukaemia; mcp.RA117.000539 HDB, Healthy donor B-cells; IGHV, Immunoglobulin heavy-chain vari- Author contributions: H.E.J., M.L., D.O., J.C.S., A.J.S., R.W., and able-region gene; MBC, Memory B-cells; M-CLL, IGHV-mutated CLL; M.S.C. designed research; H.E.J. and M.J.C. performed research; NBC, Naive B cells; NOTCH1, Neurogenic locus notch homolog H.E.J., J.C., and M.S.C. analyzed data; H.E.J., M.J.C., D.O., J.C.S., protein 1; PBMCs, Peripheral blood mononuclear cells; Rs, Regula- A.J.S., R.W., and M.S.C. wrote the paper; S.D.G. and R.W. contrib- tion score; SF3B1, Splicing factor 3B subunit 1; TMT, Tandem mass uted new reagents/analytic tools. tags; Tri12, Trisomy 12; U-CLL, IGHV-unmutated CLL. 776 Molecular & Cellular Proteomics 17.4 Proteomics of CLL Versus Healthy B-cells pathogenesis (5, 6). More recently, the DNA methylation pro- entially expressed (Ϯ1.5-fold change, p Ͻ 0.05) (21). Several file of CLL cases was shown to closely reflect that of the earlier studies provided limited proteome coverage but sug- proposed cell of origin, namely memory B-cells (MBC) and gested a number of markers of poor prognosis, such as naive B cells (NBC) for M-CLL and U-CLL, respectively. Inter- nucleophosmin, PDCD4 and TCL1 (22–27). Technological and estingly, both studies identified a third epigenetic CLL sub- methodological advances such as Orbitrap technology, iso- group with an intermediate methylation signature enriched baric labeling and two dimensional chromatography have within M-CLL with between 95 and 98% IGHV somatic mu- greatly improved proteomics coverage, leading to the first tations. These three CLL epitypes exhibit different clinico- comprehensive drafts of the human proteome (28–30). biological features, with the MBC-like CLL cases exhibiting a Our current discovery-stage study has applied isobaric la- more indolent clinical course (7–10). bels and LC-MS proteomics to the characterization of isolated Although no single aberration appears to drive disease B-cell material from 3 healthy donors and 14 CLL patients. development, many recurring gene mutations and chromo- CLL samples were selected to include a range of clinically some abnormalities have been described in CLL, and several relevant CLL subtypes associated with poor prognosis versus have prognostic and/or predictive significance. Deletion of healthy donor B-cells with the aim of assessing CLL-specific 17p and 11q which results in the loss of TP53, baculoviral IAP differential protein expression. The resulting quantitative repeat-containing 3 (BIRC3) or ataxia-telangiectasia mutated proteomes identified a strong signature common to CLL, serine/threonine kinase (ATM) respectively, are frequently as- highlighting several potential therapeutic targets and suggest- Downloaded from sociated with TP53 and ATM mutations on the remaining ing mechanisms, such as spliceosome overexpression, con- allele and poor outcome following chemo-immunotherapy tributing to pathogenesis. (11, 12). In contrast the most frequent cytogenetic abnormal- ity in CLL, deletion of 13q, results in increased expression of MATERIALS AND METHODS the anti-apoptotic protein Bcl-2, largely because of loss of Materials—SDS, HPLC and LC-MS grade ACN and formic acid http://www.mcponline.org/ miRNA15 and miR16–1, and is associated with a good prog- (FA), methyl methanethiosulfonate (MMTS), tris(2-carboxyethyl)phos- nosis, particularly in M-CLL. phine (TCEP), triethylammonium bicarbonate (TEAB), DMSO, hydrox- Other recurrent mutations also influence disease progres- ylamine were purchased from Sigma, St. Louis, Missouri. EasySep human B-cell enrichment kits without CD43 depletion were pur- sion and treatment response. Next generation sequencing chased from Stem Cell Technologies, Cambridge, UK. Tandem mass studies have confirmed that mutations of splicing factor 3B tags (TMT) 10-plex isobaric labeling reagents and 100 ␮l C18 solid subunit 1 (SF3B1) (13) and neurogenic locus notch homolog phase extraction tips were purchased from Thermo Scientific, Wal- protein 1 (NOTCH1), a transmembrane receptor and tran- tham, MA. Proteomics grade trypsin was purchased from Roche, by guest on September 20, 2018 scriptional regulator determining cell fate (14), are the most Basel, Switzerland. Fetal calf serum (FCS) was purchased from Lonza, Basel, Switzerland, lymphoprep medium from Axis-Shield Di- frequent recurring mutations in CLL, with an incidence of agnostics, Dundee, UK, and anti-human antibodies against CD3 ϳ 18% and 12%, respectively, at the time of initial treat- (OKT3) and CD19 (HIB19) from Biolegend, San Diego, CA. ment. Mutations in either gene are associated with a poorer Isolation of Healthy Donor and CLL B-cells From Clinical Sam- outcome following chemo or chemo-immunotherapy and ples—Ethical approval for the use of human samples was granted NOTCH1 mutations are also predictive of a poor response under REC references 228/02/t (Southampton) and 06/Q2202/30 to chemotherapy plus anti-CD20 antibody combinations (Bournemouth). Peripheral blood mononuclear cells (PBMCs) were derived from healthy donors and CLL patients by Southampton Blood (15, 16). Services or Bournemouth Tissue Bank, respectively. PBMCs were SF3B1 is a spliceosome component with a role in
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