title: Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia.
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.
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.|School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Powell
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Lewis
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
authors.forename: Wenying
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Toubia
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Pitman
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.|School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Wallington-Beddoe
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
authors.forename: Paul A B
authors.initials: PA
authors.lastname: Moretti
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
authors.forename: Diana
authors.initials: D
authors.lastname: Iarossi
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
authors.forename: Saumya E
authors.initials: SE
authors.lastname: Samaraweera
authors.affiliation: Department of Haematology, Alfred Hospital and Monash University, Australian Centre for Blood Diseases, Melbourne, VIC, Australia.
authors.forename: Nik
authors.initials: N
authors.lastname: Cummings
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.|School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Ramshaw
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford University, Stanford, CA; and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Department of Haematology, Alfred Hospital and Monash University, Australian Centre for Blood Diseases, Melbourne, VIC, Australia.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Wei
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.|School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: D'Andrea
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.|School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Lewis
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.|School of Medicine, University of Adelaide, Adelaide, SA, Australia.|School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Stuart M
authors.identifier: 0000-0002-9527-2740
authors.initials: SM
authors.lastname: Pitson
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000605:Amino Alcohols / Q000494:pharmacology; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D058990:Molecular Targeted Therapy; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000605:Amino Alcohols; D061945:Caspase Inhibitors; D020169:Caspases; D008246:Lysophospholipids; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D011804:Quinolines; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C579095:MCL1 protein, human; C544832:N-methyl-5-(4'-pentylphenyl)-2-aminopent-4-ene-1,3-diol; C468548:quinoline-val-asp(OMe)-CH2-OPH; C060506:sphingosine 1-phosphate