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Updated: Apr 10, 2026
Modeling Chemotherapy Resistant Leukemia In Vitro
Published on: February 9, 2016
The splicing modulator sudemycin induces a specific antitumor response and cooperates with ibrutinib in chronic
Sílvia Xargay-Torrent1, Mónica López-Guerra1,2, Laia Rosich1
1Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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.
Insights
Sudemycin, a spliceosome modulator, selectively kills chronic lymphocytic leukemia (CLL) cells by altering gene splicing. This compound shows promise as a targeted therapy for CLL, alone or combined with ibrutinib.
Area of Science:
- Oncology
- Molecular Biology
- Hematology
Background:
- Spliceosome dysfunction is implicated in tumor development.
- Chronic lymphocytic leukemia (CLL) is a B-cell malignancy where spliceosome alterations may play a role.
Purpose of the Study:
- To investigate the therapeutic potential of the spliceosome modulator sudemycin in chronic lymphocytic leukemia (CLL).
- To evaluate sudemycin's efficacy and mechanisms of action in preclinical models of CLL.
Main Methods:
- Selective cytotoxicity assays on primary CLL cells and other B-lymphoid malignancies.
- In vivo studies using NOD/SCID/IL2Rγ-/- (NSG) mice engrafted with primary CLL cells.
- Analysis of gene splicing patterns, including MCL1 and RELA, and their impact on cellular pathways.
- Combination therapy studies with ibrutinib.
Main Results:
- Sudemycin demonstrated selective cytotoxicity against primary CLL cells, particularly those with spliceosome mutations.
- Antitumor activity was observed in vivo, with sudemycin inducing apoptosis via alternative splicing of MCL1 and functionally disturbing the NF-κB pathway.
- Sudemycin induced a spliced RELA variant lacking DNA-binding domain.
- Combination of sudemycin with ibrutinib enhanced antitumor effects, potentially through modulation of IBTK splicing.
Conclusions:
- The spliceosome represents a viable therapeutic target in CLL.
- Sudemycin exhibits significant preclinical efficacy as a single agent and in combination with ibrutinib.
- Splicing modulators offer a promising therapeutic strategy for CLL treatment.
