The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1.
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.
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
M
M
Larrayoz
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
S J
SJ
Blakemore
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
R C
RC
Dobson
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
M D
MD
Blunt
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
M J J
MJ
Rose-Zerilli
Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
R
R
Walewska
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
A
A
Duncombe
Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
D
D
Oscier
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
K
K
Koide
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.|Cancer Sciences Unit, Cancer Research UK, NIHR Experimental Cancer Medicine Centres, University of Southampton, Southampton, UK.
F
F
Forconi
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
G
G
Packham
Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Japan.
M
M
Yoshida
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
M S
MS
Cragg
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
J C
JC
Strefford
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
A J
AJ
Steele
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011714:Pyrans / Q000494:pharmacology*; D012326:RNA Splicing; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics; D013141:Spiro Compounds / Q000494:pharmacology*; D059016:Tumor Microenvironment; D051020:bcl-X Protein / Q000037:antagonists & inhibitors
C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010750:Phosphoproteins; D011714:Pyrans; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; D013141:Spiro Compounds; D051020:bcl-X Protein; C553684:spliceostatin A; D015847:Interleukin-4