Repression of Fanconi anemia gene (FACC) expression inhibits growth of hematopoietic progenitor cells

Gerald M. Segal, R. Ellen Magenis, Michael Brown, Winifred Keeble, Tamara D. Smith, Michael C. Heinrich, Grover C. Bagby

    Research output: Contribution to journalArticle

    39 Scopus citations

    Abstract

    Bone marrow failure is a consistent feature of Fanconi anemia (FA) but it is not known whether the bone marrow failure is a direct and specific result of the inherited mutation or a consequence of accumulated stem cell losses resulting from nonspecific DNA damage. We tested the hypothesis that the protein encoded by the FA group C complementing gene (FACC) plays a regulatory role in hematopoiesis. We exposed normal human lymphocytes, bone marrow cells, endothelial cells, and fibroblasts to an antisense oligodeoxynucleotide (ODN) complementary to bases -4 to +14 of FACC mRNA. The mitomycin C assay demonstrated that the antisense ODN, but not missense or sense ODNs, repressed FACC gene expression in lymphocytes. Treatment with the antisense ODN substantially reduced, in a sequence-specific fashion, cytoplasmic levels of FACC mRNA in bone marrow cells and lymphocytes. Escalating doses of antisense ODN increasingly inhibited clonal growth of erythroid and granulocyte-macrophage progenitor cells but did not inhibit growth of fibroblasts or endothelial cells. The antisense ODN did not inhibit growth factor gene expression by low density bone marrow cells or marrow- derived fibroblasts. We conclude that, while the FACC gene product plays a role in defining cellular tolerance to cross-linking agents, it also functions to regulate growth, differentiation, and/or survival of normal hematopoietic progenitor cells.

    Original languageEnglish (US)
    Pages (from-to)846-852
    Number of pages7
    JournalJournal of Clinical Investigation
    Volume94
    Issue number2
    DOIs
    StatePublished - Aug 1994

    Keywords

    • DNA damage
    • antisense oligonucleotides
    • chromosome instability
    • cross-linking agent
    • hematopoiesis

    ASJC Scopus subject areas

    • Medicine(all)

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