title: Mitochondrial pro-apoptotic ARTS protein is lost in the majority of acute lymphoblastic leukemia patients.
abstract: Acquired resistance towards apoptosis is the hallmark of most if not all types of cancer. We have previously identified and characterized ARTS, a broadly expressed protein localized to mitochondria. ARTS was initially shown to mediate TGF-beta induced apoptosis. Recently, we have found that high levels of ARTS induce apoptosis without additional pro-apoptotic stimuli. Further, ARTS promotes apoptosis in response to a wide variety of pro-apoptotic stimuli. Here, we report that the expression of ARTS is lost in all lymphoblasts of more than 70% of childhood acute lymphoblastic leukemia (ALL) patients. The loss of ARTS is specific, as the related non-apoptotic protein H5, bearing 83% identity to ARTS, is unaffected. During remission, ARTS expression is detected again in almost all patients. Two leukemic cell lines, ALL-1 and HL-60 lacking ARTS, were resistant to apoptotic induction by ara-C. Transfection of ARTS into these cells restored their ability to undergo apoptosis in response to this chemotherapeutic agent. We found that methylation process contributes to the loss of ARTS expression. We conclude that the loss of ARTS may provide a selective advantage for cells to escape apoptosis thereby contributing to their transformation to malignant lymphoblasts. We therefore propose that ARTS can function as a tumor suppressor protein in childhood ALL.
authors.affiliation: Pediatric-Hemato-Oncology Department, Rambam Medical Center, Bat-Galim, Haifa 31096, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Elhasid
authors.forename: Dvora
authors.initials: D
authors.lastname: Sahar
authors.forename: Ayellet
authors.initials: A
authors.lastname: Merling
authors.forename: Yifat
authors.initials: Y
authors.lastname: Zivony
authors.forename: Asaf
authors.initials: A
authors.lastname: Rotem
authors.forename: Miriam
authors.initials: M
authors.lastname: Ben-Arush
authors.forename: Shai
authors.initials: S
authors.lastname: Izraeli
authors.forename: Dani
authors.initials: D
authors.lastname: Bercovich
authors.forename: Sarit
authors.initials: S
authors.lastname: Larisch
mesh_terms: D001853:Bone Marrow / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D012333:RNA, Messenger / Q000097:blood / Q000378:metabolism; D058112:Septins
chemical_list: D003598:Cytoskeletal Proteins; D012333:RNA, Messenger; D020558:GTP Phosphohydrolases; C492027:SEPTIN4 protein, human; D058112:Septins