SYM-31-02

Targeting sphingosine kinase 1 induces MCL-1 dependent cell death in acute myeloid leukemia

SM Pitson

Centre for Cancer Biology, University of South Australia and SA Pathology, Frome Road, Adelaide SA 5000

Acute myeloid leukaemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy and bone marrow transplantation, overall survival remains poor. Sphingosine kinase 1 (SK1) generates the bioactive lipid sphingosine 1-phosphate (S1P) and has established roles in tumour initiation, progression and chemotherapy resistance in a wide range of cancers. The role and targeting of SK1 in primary AML, however, has not been previously investigated. Here we show that SK1 is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SK1 induced caspase-dependant cell death in AML cell lines, primary AML patient blasts, and isolated AML patient leukaemic progenitor/stem cells, with negligible effects on normal bone marrow CD34+ progenitors from healthy donors. Furthermore, administration of SK1 inhibitors to orthotopic AML patient-derived xenografts reduced tumour burden and prolonged overall survival without affecting murine haematopoiesis. SK1 inhibition was associated with reduced survival signalling from S1P receptor 2, resulting in selective down-regulation of the pro-survival protein Mcl-1. Subsequent analysis showed combination of BH3 mimetics with either SK1 inhibition or S1P receptor 2 antagonism triggered synergistic AML cell death. These results support the notion that SK1 is a bone fide therapeutic target for the treatment of AML.