Mitochondrial pro-apoptotic ARTS protein is lost in the majority of acute lymphoblastic leukemia patients

Ronit Elhasid, Dvora Sahar, Ayellet Merling, Yifat Zivony, Asaf Rotem, Miriam Ben-Arush, Shai Izraeli, Dani Bercovich, Sarit Larisch*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

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-β 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 proapoptotic 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 fraction as a tumor suppressor protein in childhood ALL.

Original languageEnglish
Pages (from-to)5468-5475
Number of pages8
JournalOncogene
Volume23
Issue number32
DOIs
StatePublished - 15 Jul 2004

Funding

FundersFunder number
Israel Cancer Association
Israel Science Foundation

    Keywords

    • ARTS
    • Apoptosis
    • Leukemia
    • Mitochandria

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