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Chronic lymphocytic leukemia

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

Leukemia volume 30, pages 351–360 (2016)Cite this article

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Abstract

The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukaemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA) is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose- and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression. However, normal B and T cells were less sensitive than CLL cells (P=0.006 and P<0.001, respectively). SSA altered the splicing of anti-apoptotic MCL-1L to MCL-1s in CLL cells coincident with induction of apoptosis. Overexpression studies in Ramos cells suggested that Mcl-1 was important for SSA-induced killing since its expression inversely correlated with apoptosis (P=0.001). IL4 and CD40L, present in patient lymph nodes, are known to protect tumour cells from apoptosis and significantly inhibited SSA, ABT-263 and ABT-199 induced killing following administration to CLL cells (P=0.008). However, by combining SSA with the Bcl-2/Bcl-xL antagonists ABT-263 or ABT-199, we were able to overcome this pro-survival effect. We conclude that SSA combined with Bcl-2/Bcl-xL antagonists may have therapeutic utility for CLL.

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Acknowledgements

We thank Leukaemia and Lymphoma Research (12036, 12021), for supporting this work, the patients for supplying tissue and the infrastructure support from a CR-UK centre grant (C34999/A18087). We thank Astellas Pharmaceuticals for supplying FR901464 for SSA synthesis by Professor Yoshida, and Dr Duriez, Mr Tracy and Mrs Henderson for technical support (LLR grant 12021, ECMC C24563/A15581). The synthesis of meayamycin B was supported by the US National Institutes of Health (R01 CA120792) to Professor Koide.

Author contributions

ML, MY, MSC, JCS and AJS designed and analysed experiments and wrote the manuscript. ML, SJB, RD, MJJR and MDB performed experimental work. MY and KK synthesized SSA and meayamycin B, respectively. FF, RW, AD and DO obtained patient consent and analysed clinical data. DO, MY, KK and GP provided critical review.

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Author notes

  1. M S Cragg, J C Strefford and A J Steele: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK

    M Larrayoz, S J Blakemore, R C Dobson, M D Blunt, M J J Rose-Zerilli, A Duncombe, F Forconi, G Packham, M S Cragg, J C Strefford & A J Steele

  2. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK

    R Walewska & D Oscier

  3. Department of Chemistry, University of Pittsburgh, Pittsburgh,, PA, USA

    K Koide

  4. Cancer Sciences Unit, Cancer Research UK, NIHR Experimental Cancer Medicine Centres, University of Southampton, Southampton, UK

    F Forconi

  5. Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Japan

    M Yoshida

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  1. M Larrayoz
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Larrayoz, M., Blakemore, S., Dobson, R. et al. The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1. Leukemia 30, 351–360 (2016). https://doi.org/10.1038/leu.2015.286

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