TY - JOUR
T1 - Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia
AU - Powell, Jason
AU - Lewis, Alexander
AU - Zhu, Wenying
AU - Toubia, John
AU - Pitman, Melissa
AU - Wallington-Beddoe, Craig
AU - Moretti, Paul
AU - Larossi, Diana
AU - Samaraweera, Saumya
AU - Cummings, Nick
AU - Ramshaw, Hayley
AU - Thomas, Daniel
AU - Wei, Andrew
AU - Lopez, Angel
AU - Richardson, Andrea
AU - Lewis, Ian
AU - Pitson, Stuart
PY - 2017/2/9
Y1 - 2017/2/9
N2 - Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy andbonemarrowtransplantation, overall survival remains poor. Sphingosine kinase 1 (SPHK1) generates the bioactive lipid sphingosine 1- phosphate (S1P) and has established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers. The role and targeting of SPHK1 in primaryAML, however, has not been previously investigated. HereweshowthatSPHK1is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SPHK1 induced caspase-dependent cell death inAMLcell lines, primaryAMLpatient blasts, and isolatedAMLpatient leukemic progenitor/stem cells, with negligible effects on normal bone marrow CD34+ progenitors from healthy donors. Furthermore, administration of SPHK1 inhibitors to orthotopic AML patient-derived xenografts reduced tumor burden and prolonged overall survival without affecting murine hematopoiesis. SPHK1 inhibition was associated with reduced survival signaling from S1P receptor 2, resulting in selective downregulation of the prosurvival protein MCL1. Subsequent analysis showed that the combination of BH3 mimetics with either SPHK1 inhibition or S1P receptor 2 antagonism triggered synergistic AML cell death. These results support the notion that SPHK1 is a bona fide therapeutic target for the treatment of AML.
AB - Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy andbonemarrowtransplantation, overall survival remains poor. Sphingosine kinase 1 (SPHK1) generates the bioactive lipid sphingosine 1- phosphate (S1P) and has established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers. The role and targeting of SPHK1 in primaryAML, however, has not been previously investigated. HereweshowthatSPHK1is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SPHK1 induced caspase-dependent cell death inAMLcell lines, primaryAMLpatient blasts, and isolatedAMLpatient leukemic progenitor/stem cells, with negligible effects on normal bone marrow CD34+ progenitors from healthy donors. Furthermore, administration of SPHK1 inhibitors to orthotopic AML patient-derived xenografts reduced tumor burden and prolonged overall survival without affecting murine hematopoiesis. SPHK1 inhibition was associated with reduced survival signaling from S1P receptor 2, resulting in selective downregulation of the prosurvival protein MCL1. Subsequent analysis showed that the combination of BH3 mimetics with either SPHK1 inhibition or S1P receptor 2 antagonism triggered synergistic AML cell death. These results support the notion that SPHK1 is a bona fide therapeutic target for the treatment of AML.
UR - http://www.scopus.com/inward/record.url?scp=85015282085&partnerID=8YFLogxK
U2 - 10.1182/blood-2016-06-720433
DO - 10.1182/blood-2016-06-720433
M3 - Article
SN - 0006-4971
VL - 129
SP - 771
EP - 782
JO - Blood
JF - Blood
IS - 6
ER -