REPRESSION OF FANCONI-ANEMIA GENE (FACC) EXPRESSION INHIBITS GROWTH OF HEMATOPOIETIC PROGENITOR CELLS

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 speci fic result of the inherited mutation or a consequence of accumulated s tem cell losses resulting from nonspecific DNA damage. We tested the h ypothesis that the protein encoded by the FA group C complementing gen e (FACC) plays a regulatory role in hematopoiesis. We exposed normal h uman lymphocytes, bone marrow cells, endothelial cells, and fibroblast s to an antisense oligodeoxynucleotide (ODN) complementary to bases -4 to +14 of FACC mRNA. The mitomycin C assay demonstrated that the anti sense ODN, but not missense or sense ODNs, repressed FACC gene express ion in lymphocytes. Treatment with the antisense ODN substantially red uced, in a sequence-specific fashion, cytoplasmic levels of FACC mRNA in bone marrow cells and lymphocytes. Escalating doses of antisense OD N increasingly inhibited clonal growth of erythroid and granulocyte-ma crophage progenitor cells but did not inhibit growth of fibroblasts or endothelial cells. The antisense ODN did not inhibit growth factor ge ne expression by low density bone marrow cells or marrow-derived fibro blasts. 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 hemato poietic progenitor cells.