title: Therapeutic efficacy of FTY720 in a rat model of NK-cell leukemia.
abstract: NK-cell leukemia is a clonal expansion of NK cells. The illness can occur in an aggressive or chronic form. We studied cell lines from human and rat NK-cell leukemias (aggressive NK-cell leukemia) as well as samples from patients with chronic NK-cell leukemia to investigate pathogenic mechanisms. Here we report that Mcl-1 was overexpressed in leukemic NK cells and that knockdown of Mcl-1 induced apoptosis in these leukemic cells. In vitro treatment of human and rat NK leukemia cells with FTY720 led to caspase-dependent apoptosis and decreased Mcl-1 expression in a time- and-dose-dependent manner. These biologic effects could be inhibited by blockade of reactive oxygen species generation and the lysosomal degradation pathway. Lipidomic analyses after FTY720 treatment demonstrated elevated levels of sphingosine, which mediated apoptosis of leukemic NK cells in vitro. Importantly, systemic administration of FTY720 induced complete remission in the syngeneic Fischer rat model of NK-cell leukemia. Therapeutic efficacy was associated with decreased expression of Mcl-1 in vivo. These data demonstrate that therapeutic benefit of FTY720 may result from both altered sphingolipid metabolism as well as enhanced degradation of a key component of survival signaling.
authors.affiliation: Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Aijun
authors.initials: A
authors.lastname: Liao
authors.forename: Kathleen
authors.initials: K
authors.lastname: Broeg
authors.forename: Todd
authors.initials: T
authors.lastname: Fox
authors.forename: Su-Fern
authors.initials: SF
authors.lastname: Tan
authors.forename: Rebecca
authors.initials: R
authors.lastname: Watters
authors.forename: Mithun Vinod
authors.initials: MV
authors.lastname: Shah
authors.forename: Lucy Q
authors.initials: LQ
authors.lastname: Zhang
authors.forename: Yongping
authors.initials: Y
authors.lastname: Li
authors.forename: Lindsay
authors.initials: L
authors.lastname: Ryland
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Cesar
authors.initials: C
authors.lastname: Aliaga
authors.forename: Alden
authors.initials: A
authors.lastname: Dewey
authors.forename: Andrew
authors.initials: A
authors.lastname: Rogers
authors.forename: Kelly
authors.initials: K
authors.lastname: Loughran
authors.forename: Leah
authors.initials: L
authors.lastname: Hirsch
authors.forename: Nancy Ruth
authors.initials: NR
authors.lastname: Jarbadan
authors.forename: Kendall Thomas
authors.initials: KT
authors.lastname: Baab
authors.forename: Jason
authors.initials: J
authors.lastname: Liao
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.forename: Mark
authors.initials: M
authors.lastname: Kester
authors.forename: Dhimant
authors.initials: D
authors.lastname: Desai
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D007938:Leukemia / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011409:Propylene Glycols / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011409:Propylene Glycols; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine