Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/105382
Title: The splicing modulator sudemycin induces a specific antitumor response and cooperates with ibrutinib in chronic lymphocytic leukemia
Author: Xargay i Torrent, Sílvia
López Guerra, Mónica
Rosich, Laia
Montraveta, Arnau
Roldán, Jocabed
Rodríguez, Vanina
Villamor i Casas, Neus
Aymerich Gregorio, Marta
Lagisetti, Chandraiah
Webb, Thomas R.
López Otín, Carlos
Campo Güerri, Elias
Colomer Pujol, Dolors
Keywords: Leucèmia limfocítica crònica
Limfomes
Medicaments
Tumors
Marcadors bioquímics
Chronic lymphocytic leukemia
Lymphomas
Drugs
Tumors
Biochemical markers
Issue Date: 8-Jun-2015
Publisher: Impact Journals
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.
Note: Reproducció del document publicat a: https://doi.org/10.18632/oncotarget.4212
It is part of: Oncotarget, 2015, vol. 6, num. 26, p. 22734-22749
Related resource: https://doi.org/10.18632/oncotarget.4212
URI: http://hdl.handle.net/2445/105382
ISSN: 1949-2553
Appears in Collections:Articles publicats en revistes (Fonaments Clínics)

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