1. Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia
- Author
-
Saumya E. Samaraweera, Diana Iarossi, Alexander C. Lewis, Ian D. Lewis, Angel F. Lopez, Melissa R. Pitman, Richard J D'Andrea, Andrew H. Wei, Hayley S. Ramshaw, Craig T. Wallington-Beddoe, John Toubia, Stuart M. Pitson, Jason A. Powell, Wenying Zhu, Nik Cummings, Daniel Thomas, Paul A.B. Moretti, Powell, Jason A, Lewis, Alexander C, Zhu, Wenying, Toubia, John, Pitman, Melissa R, Wallington-Beddoe, Craig T, Moretti, Paul AB, Iarossi, Diana, Samaraweera, Saumya E, Cummings, Nik, Ramshaw, Hayley S, Thomas, Daniel, Wei, Andrew H, Lopez, Angel F, D'Andrea, Richard J, Lewis, Ian D, and Pitson, Stuart M
- Subjects
0301 basic medicine ,Myeloid ,CD34 ,Biochemistry ,myeloid leukemia ,Amino Acid Chloromethyl Ketones ,Mice ,chemistry.chemical_compound ,Mice, Inbred NOD ,Sphingosine ,hemic and lymphatic diseases ,Molecular Targeted Therapy ,human AML cells ,Myeloid Neoplasia ,Cell Death ,biology ,Gene Expression Regulation, Leukemic ,Myeloid leukemia ,Hematology ,Amino Alcohols ,Caspase Inhibitors ,Leukemia, Myeloid, Acute ,Phosphotransferases (Alcohol Group Acceptor) ,Receptors, Lysosphingolipid ,Leukemia ,xenografts ,medicine.anatomical_structure ,Sphingosine kinase 1 ,Caspases ,Neoplastic Stem Cells ,Quinolines ,Female ,Signal Transduction ,Immunology ,Bone Marrow Cells ,SPHK1 ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,aspase-dependent cell death ,Animals ,Humans ,Progenitor cell ,Protein Kinase Inhibitors ,MCL1 degradation ,Cell Biology ,medicine.disease ,Survival Analysis ,Xenograft Model Antitumor Assays ,Myeloid Cell Leukemia Sequence 1 Protein ,030104 developmental biology ,chemistry ,Cancer research ,biology.protein ,Lysophospholipids - 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. 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, 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 down regulation 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. Refereed/Peer-reviewed
- Published
- 2017
- Full Text
- View/download PDF