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|Title:||Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia.|
|Citation:||Blood, 2017; 129(6):771-782|
|Publisher:||American Society of Hematology|
|Jason A. Powell, Alexander C. Lewis, Wenying Zhu, John Toubia, Melissa R. Pitman, Craig T. Wallington-Beddoe, Paul A. B. Moretti, Diana Iarossi, Saumya E. Samaraweera, Nik Cummings, Hayley S. Ramshaw, Daniel Thomas, Andrew H. Wei, Angel F. Lopez, Richard J. D’Andrea, Ian D. Lewis and Stuart M. Pitson|
|Abstract:||Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy and bone marrow transplantation, 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 primary AML, however, has not been previously investigated. Here we show that SPHK1 is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SPHK1 induced caspase-dependent cell death in AML cell lines, primary AML patient blasts, and isolated AML patient 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.|
|Keywords:||Bone Marrow Cells; Cell Line, Tumor; Animals; Mice, Inbred NOD; Humans; Mice; Amino Alcohols; Sphingosine; Quinolines; Caspases; Phosphotransferases (Alcohol Group Acceptor); Lysophospholipids; Amino Acid Chloromethyl Ketones; Receptors, Lysosphingolipid; Protein Kinase Inhibitors; Survival Analysis; Xenograft Model Antitumor Assays; Signal Transduction; Cell Death; Gene Expression Regulation, Leukemic; Female; Neoplastic Stem Cells; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Caspase Inhibitors; Myeloid Cell Leukemia Sequence 1 Protein|
|Rights:||© 2017 by The American Society of Hematology|
|Appears in Collections:||Medicine publications|
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