title: The splicing modulator sudemycin induces a specific antitumor response and cooperates with ibrutinib in chronic lymphocytic leukemia.
abstract: Mutations or deregulated expression of the components of the spliceosome can influence the splicing pattern of several genes and contribute to the development of tumors. In this context, we report that the spliceosome modulator sudemycin induces selective cytotoxicity in primary chronic lymphocytic leukemia (CLL) cells when compared with healthy lymphocytes and tumor cells from other B-lymphoid malignancies, with a slight bias for CLL cases with mutations in spliceosome-RNA processing machinery. Consistently, sudemycin exhibits considerable antitumor activity in NOD/SCID/IL2Rγ-/- (NSG) mice engrafted with primary cells from CLL patients. The antileukemic effect of sudemycin involves the splicing modulation of several target genes important for tumor survival, both in SF3B1-mutated and -unmutated cases. Thus, the apoptosis induced by this compound is related to the alternative splicing switch of MCL1 toward its proapoptotic isoform. Sudemycin also functionally disturbs NF-κB pathway in parallel with the induction of a spliced RELA variant that loses its DNA binding domain. Importantly, we show an enhanced antitumor effect of sudemycin in combination with ibrutinib that might be related to the modulation of the alternative splicing of the inhibitor of Btk (IBTK). In conclusion, we provide first evidence that the spliceosome is a relevant therapeutic target in CLL, supporting the use of splicing modulators alone or in combination with ibrutinib as a promising approach for the treatment of CLL patients.
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Xargay-Torrent
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Hematopathology Unit, Department of Pathology, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: López-Guerra
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Rosich
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Montraveta
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Jocabed
authors.initials: J
authors.lastname: Roldán
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Vanina
authors.initials: V
authors.lastname: Rodríguez
authors.affiliation: Hematopathology Unit, Department of Pathology, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Villamor
authors.affiliation: Hematopathology Unit, Department of Pathology, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Aymerich
authors.affiliation: Center for Chemical Biology, Biosciences Division, SRI International, Menlo Park, California, USA.
authors.forename: Chandraiah
authors.initials: C
authors.lastname: Lagisetti
authors.affiliation: Center for Chemical Biology, Biosciences Division, SRI International, Menlo Park, California, USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Webb
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo - IUOPA, Oviedo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.affiliation: Hematopathology Unit, Department of Pathology, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Hematopathology Unit, Department of Pathology, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003514:Cyclohexylamines / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D010880:Piperidines; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D012326:RNA Splicing; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D017381:Spliceosomes / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C586721:5-((4-(5-(7,7-dimethyl-1,6-dioxaspiro(2.5)octan-5-yl)-3-methylpenta-2,4-dien-1-yl)cyclohexyl)amino)-5-oxopent-3-en-2-yl methylcarbamate; D003514:Cyclohexylamines; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D013141:Spiro Compounds; C551803:ibrutinib; D000225:Adenine
keywords: SF3B1; chronic lymphocytic leukemia; ibrutinib; spliceosome; sudemycin