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 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.
Segal
G M
GM
Department of Medicine, Oregon Health Sciences University, Portland 97201-3098.
Magenis
R E
RE
Brown
M
M
Keeble
W
W
Smith
T D
TD
Heinrich
M C
MC
Bagby
G C
GC
D001483:Base Sequence; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins; D005199:Fanconi Anemia / Q000235:genetics*; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D015870:Gene Expression / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011506:Proteins / Q000235:genetics / Q000502:physiology*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011506:Proteins; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor