Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia.

Autor:	Powell JA; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.; School of Medicine, University of Adelaide, Adelaide, SA, Australia., Lewis AC; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia., Zhu W; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia., Toubia J; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia., Pitman MR; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia., Wallington-Beddoe CT; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.; School of Medicine, University of Adelaide, Adelaide, SA, Australia., Moretti PA; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia., Iarossi D; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia., Samaraweera SE; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia., Cummings N; Department of Haematology, Alfred Hospital and Monash University, Australian Centre for Blood Diseases, Melbourne, VIC, Australia., Ramshaw HS; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.; School of Medicine, University of Adelaide, Adelaide, SA, Australia., Thomas D; Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford University, Stanford, CA; and., Wei AH; Department of Haematology, Alfred Hospital and Monash University, Australian Centre for Blood Diseases, Melbourne, VIC, Australia., Lopez AF; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.; School of Medicine, University of Adelaide, Adelaide, SA, Australia., D'Andrea RJ; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia., Lewis ID; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.; School of Medicine, University of Adelaide, Adelaide, SA, Australia., Pitson SM; 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.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2017 Feb 09; Vol. 129 (6), pp. 771-782. Date of Electronic Publication: 2016 Dec 12.
DOI:	10.1182/blood-2016-06-720433
Abstrakt:	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. (© 2017 by The American Society of Hematology.)
Databáze:	MEDLINE
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