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SF3B1-Mutated Chronic Lymphocytic Leukemia Shows Evidence Of

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SF3B1-mutated chronic lymphocytic leukemia shows evidence of NOTCH1 pathway activation including CD20 downregulation by Federico Pozzo, Tamara Bittolo, Erika Tissino, Filippo Vit, Elena Vendramini, Luca Laurenti, Giovanni D'Arena, Jacopo Olivieri, Gabriele Pozzato, Francesco Zaja, Annalisa Chiarenza, Francesco Di Raimondo, Antonella Zucchetto, Riccardo Bomben, Francesca Maria Rossi, Giovanni Del Poeta, Michele Dal Bo, and Valter Gattei Haematologica 2020 [Epub ahead of print] Citation: Federico Pozzo, Tamara Bittolo, Erika Tissino, Filippo Vit, Elena Vendramini, Luca Laurenti, Giovanni D'Arena, Jacopo Olivieri, Gabriele Pozzato, Francesco Zaja, Annalisa Chiarenza, Francesco Di Raimondo, Antonella Zucchetto, Riccardo Bomben, Francesca Maria Rossi, Giovanni Del Poeta, Michele Dal Bo, and Valter Gattei SF3B1-mutated chronic lymphocytic leukemia shows evidence of NOTCH1 pathway activation including CD20 downregulation. Haematologica. 2020; 105:xxx doi:10.3324/haematol.2020.261891 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process. SF3B1-mutated chronic lymphocytic leukemia shows evidence of NOTCH1 pathway activation including CD20 downregulation Federico Pozzo1, Tamara Bittolo1, Erika Tissino1, Filippo Vit1,2, Elena Vendramini1, Luca Laurenti3, Giovanni D’Arena4, Jacopo Olivieri5, Gabriele Pozzato6, Francesco Zaja6, Annalisa Chiarenza7, Francesco Di Raimondo7, Antonella Zucchetto1, Riccardo Bomben1, Francesca Maria Rossi1, Giovanni Del Poeta8, Michele Dal Bo1 and Valter Gattei1. 1 Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN), Italy; 2 University of Trieste, Trieste, Italy; 3 Hematology Institute, Catholic University of the Sacred Heart, Fondazione Policlinico A. Gemelli, Rome, Italy; 4 Hematology Service, S. Luca Hospital, Vallo Della Lucania (SA), Italy; 5Clinica Ematologica, Centro Trapianti e Terapie Cellulari "Carlo Melzi", Azienda Sanitaria Universitaria Integrata di Udine, Italy; 6 Department of Internal Medicine and Hematology, Maggiore General Hospital, University of Trieste, Trieste, Italy; 7 Division of Hematology, Ferrarotto Hospital, Catania, Italy; 8 Division of Hematology, S. Eugenio Hospital and University of Tor Vergata, Rome, Italy. Correspondence: Federico Pozzo, PhD, or Valter Gattei, MD, Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Via Franco Gallini 2, ZIP code 33081, Aviano (PN), Italy Tel: 0039-0434-659719 Tel: 0039-0434-659410 Fax: 0039-0434-659409 e-mail: [email protected]; [email protected] Running title: SF3B1 mutations and NOTCH1 activation in CLL Keywords: CLL, SF3B1, NOTCH1, CD20 Conflict of interest disclosure: The Authors declare no competing financial interests. Financial Support Michele dal Bo:Progetto Giovani Ricercatori, GR-2011-02351370, Ministero della Salute, Rome, Italy; Progetto Ricerca Finalizzata PE-2016-02362756, Ministero della Salute, Rome, Italy; Antonella Zucchetto: Progetto Ricerca Finalizzata RF-2018-12365790, Ministero della Salute, Rome, Italy; Valter Gattei: Associazione Italiana Ricerca Cancro (AIRC), Investigator Grant IG-2018 (21687); Linfo- check - Bando ricerca - contributo art. 15, comma 2, lett b) LR 17/2014; Associazione Italiana contro le Leucemie, linfomi e mielomi (AIL), Venezia Section, Pramaggiore Group, Italy; “5x1000 Intramural Program”, Centro di Riferimento Oncologico, Aviano, Italy. Word count: 3964 Figure count: 5 Supplementary Files count: 1 1 Summary Chronic lymphocytic leukemia (CLL) is characterized by a low CD20 expression, in part explained by epigenetic alterations induced by activation of the NOTCH1 pathway. The study provides evidence that CLL cases carrying mutations of the SF3B1 gene show features of NOTCH1 activation including the concomitant down-regulation of surface CD20, correlating with splicing alterations of the NOTCH1 negative regulator DVL2. Abstract Chronic lymphocytic leukemia (CLL) is characterized by a low CD20 expression, in part explained by an epigenetic-driven downregulation triggered by mutations of the NOTCH1 gene. In the present study, by taking advantage of a wide and well-characterized CLL cohort (n=537), we demonstrate that CD20 expression is downregulated in SF3B1-mutated CLL in an extent similar to NOTCH1-mutated CLL. In fact, SF3B1-mutated CLL cells show common features with NOTCH1-mutated CLL cells, including a gene expression profile enriched of NOTCH1-related gene sets and elevated expression of the active intra- cytoplasmic NOTCH1. Activation of the NOTCH1 signaling and down-regulation of surface CD20 in SF3B1-mutated CLL cells correlate with over-expression of an alternatively spliced form of DVL2, a component of the Wnt pathway and negative regulator of the NOTCH1 pathway. These findings are confirmed by separately analyzing the CD20-dim and CD20-bright cell fractions from SF3B1-mutated cases as well as by DVL2 knock-out experiments in CLL-like cell models. Altogether, the clinical and biological features that characterize NOTCH1-mutated CLL may also be recapitulated in SF3B1-mutated CLL, contributing to explain the poor prognosis of this CLL subset and providing the rationale for expanding novel agents-based therapies to SF3B1-mutated CLL. 2 Introduction Chronic lymphocytic leukemia (CLL) is characterized by a high clinical and biological heterogeneity.1 Therapy regimens that include monoclonal antibodies against CD20 are widely used, both as single agent and in combination2,3 although, in specific CLL subsets, the efficacy of anti-CD20 therapy may be reduced by the peculiar dimmer expression of CD20 in CLL4-6 compared to other lymphoproliferative disorders.7 A number of factors have been variously associated with CD20 regulation, e.g. NF-kB signaling, CXCR4 pathway, BCR signaling, histone deacetylases and activity of multiple transcription factors (such as IRF4, NF-kB, PU.1, OCT1/2);8 in addition, CD20 expression in CLL can be also affected by mutations of the NOTCH1 gene whose presence, detected in up to 25% of cases,9 has been associated with clinical resistance to anti-CD20 immunotherapy both in clinical trials and real-world scenarios.10-12 We previously demonstrated that the reduction of CD20 expression in NOTCH1-mutated CLL cells could be due to a NOTCH1 mutation-driven epigenetic dysregulation involving histone deacetylases.5,13 Although genetic mutations represent the main contributor to the aberrant activation of the NOTCH1 pathway in CLL,14 a mutation-independent activation was also reported for a significant fraction of NOTCH1-unmutated cases.15 In that setting, however, nothing is known regarding the mechanism(s) behind the activation of NOTCH1 and the concomitant modulation of CD20 expression. Another recurrently mutated gene in CLL is the RNA splicing factor 3b subunit 1 (SF3B1), found mutated in about 10% CLL cases.16-19 SF3B1 is a key component of the splicing machinery, responsible of recognizing the branchpoint sequences in proximity of the 3′ splice site (acceptor site) allowing intron removal from precursor-messenger RNAs. Mutations are predicted to alter the protein’s tertiary structure, hampering the correct high-affinity recognition of the branchpoint sequences and resulting in the selection of alternative 3 splice sites. This leads to aberrantly spliced transcripts, gain/change/loss-of-function variants, novel stop codons or downregulation of gene expression through nonsense-mediated decay.20-23 In CLL, mutations of SF3B1 have been shown to induce transcriptome-wide alterations of splicing patterns, resulting in an increased frequency of alternative 3′ splice site selection, with functional consequences on several pathways such as DNA damage, telomere maintenance and, possibly, NOTCH1 signaling,18,19,23,24 although the actual impact of SF3B1 mutations in the pathobiology of CLL remains to be fully elucidated. In the present study, by taking advantage of a large cohort of primary CLL cases, we demonstrated that SF3B1-mutated CLL have features of NOTCH1 pathway activation and NOTCH1-dependent CD20 downregulation. 3 Methods Primary CLL cells The study is part of a comprehensive CLL characterization approved by the Internal Review Board of the Centro di Riferimento Oncologico di Aviano (Approvals n. IRB-05-2010, n. IRB-05-2015) upon informed consent in accordance with the declaration of Helsinki, and included peripheral blood samples from 537 CLL patients (Supplementary Table 1).1,25 Primary CLL cells were separated by Ficoll-Hypaque (GE Healthcare, Uppsala, Sweden) density gradient centrifugation and either used directly or cryopreserved until use. All studies were performed on highly purified cells (>95% pure). CLL cases were characterized for IGHV mutational status, the main cytogenetic abnormalities, CD49d expression and mutational status of TP53 as described.26,27 In 382/537 cases, time-to-first-treatment (TTFT)
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