The splicing modulator sudemycin induces a specific antitumor response and cooperates with ibrutinib in chronic lymphocytic leukemia
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Sílvia Xargay-Torrent1,*, Mónica López-Guerra1,2,*, Laia Rosich1, Arnau Montraveta1, Jocabed Roldán1, Vanina Rodríguez1, Neus Villamor2, Marta Aymerich2, Chandraiah Lagisetti3, Thomas R. Webb3, Carlos López-Otín4, Elias Campo2, Dolors Colomer1,2
1Experimental Therapeutics in Lymphoid Malignancies Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
2Hematopathology Unit, Department of Pathology, Hospital Clinic, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
3Center for Chemical Biology, Biosciences Division, SRI International, Menlo Park, California, USA
4Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo - IUOPA, Oviedo, Spain
*These authors have contributed equally to this work
Dolors Colomer, e-mail: firstname.lastname@example.org
Keywords: SF3B1, chronic lymphocytic leukemia, sudemycin, ibrutinib, spliceosome
Received: May 15, 2015 Accepted: May 26, 2015 Published: June 08, 2015
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.
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