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

  • Leukemia. 2016 Feb;30(2):351-60. doi: 10.1038/leu.2015.286.
M Larrayoz  1 ,  S J Blakemore  1 ,  R C Dobson  1 ,  M D Blunt  1 ,  M J J Rose-Zerilli  1 ,  R Walewska  2 ,  A Duncombe  1 ,  D Oscier  2 ,  K Koide  3 ,  F Forconi  1  4 ,  G Packham  1 ,  M Yoshida  5 ,  M S Cragg  1 ,  J C Strefford  1 ,  A J Steele  1
Affiliations
  • 1. Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
  • 2. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
  • 3. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
  • 4. Cancer Sciences Unit, Cancer Research UK, NIHR Experimental Cancer Medicine Centres, University of Southampton, Southampton, UK.
  • 5. Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Japan.
PMID: 26488112 DOI: 10.1038/leu.2015.286
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-1(L) to Mcl-1(s) 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-x(L) antagonists ABT-263 or ABT-199, we were able to overcome this pro-survival effect. We conclude that SSA combined with Bcl-2/Bcl-x(L) antagonists may have therapeutic utility for CLL.

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