title: Sphingosine kinase 2 promotes acute lymphoblastic leukemia by enhancing MYC expression.
abstract: Sphingosine kinase 2 (SK2) may have utility as a prognostic marker in inflammatory diseases such as cancer in which it has been rationalized as a candidate therapeutic target. Here, we show that SK2 has an oncogenic role in acute lymphoblastic leukemia (ALL) by influencing expression of MYC. Genetic ablation of SK2 impaired leukemia development in a mouse model of ALL and pharmacologic inhibition extended survival in mouse xenograft models of human disease. SK2 attenuation in both the settings reduced MYC expression in leukemic cells, with reduced levels of acetylated histone H3 within the MYC gene associated with reduced levels of MYC protein and expression of MYC-regulated genes. Our results demonstrated that SK2 regulates MYC, which has a pivotal role in hematologic malignancies, providing a preclinical proof of concept for this pathway as a broad-based therapeutic target in this setting.
authors.affiliation: Authors' Affiliations: Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney; Hematology Department, Westmead Hospital, Westmead, Sydney, New South Wales; and Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Wallington-Beddoe
authors.affiliation: Authors' Affiliations: Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney; Hematology Department, Westmead Hospital, Westmead, Sydney, New South Wales; and Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Powell
authors.affiliation: Authors' Affiliations: Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney; Hematology Department, Westmead Hospital, Westmead, Sydney, New South Wales; and Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors.forename: Daochen
authors.initials: D
authors.lastname: Tong
authors.affiliation: Authors' Affiliations: Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney; Hematology Department, Westmead Hospital, Westmead, Sydney, New South Wales; and Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pitson
authors.affiliation: Authors' Affiliations: Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney; Hematology Department, Westmead Hospital, Westmead, Sydney, New South Wales; and Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bradstock
authors.affiliation: Authors' Affiliations: Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney; Hematology Department, Westmead Hospital, Westmead, Sydney, New South Wales; and Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia linda.bendall@sydney.edu.au.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bendall
mesh_terms: D000107:Acetylation; D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic; D016259:Genes, myc; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
chemical_list: D000218:Adamantane; D020169:Caspases; D004791:Enzyme Inhibitors; D006657:Histones; D017853:Phosphotransferases (Alcohol Group Acceptor); D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D000099157:Sphingosine Kinase; C489427:MYC protein, human; C548780:3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide