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Blood, 15 May 2001, Vol. 97, No. 10, pp. 3017-3024
HEMATOPOIESIS
Functional correction of FA-C cells with
FANCC suppresses the expression of
interferon  -inducible genes
Sara R. Fagerlie,
Jane Diaz,
Tracy A. Christianson,
Kelli McCartan,
Winifred Keeble,
Gregory R. Faulkner, and
Grover C. Bagby
From the Division of Hematology and Medical Oncology,
the Department of Molecular and Medical Genetics, and the Oregon Cancer
Center, Oregon Health Sciences University; and the Molecular
Hematopoiesis Laboratory, VA Medical Center, Portland, OR.
Because hematopoietic cells derived from Fanconi anemia (FA)
patients of the C-complementation group (FA-C) are hypersensitive to
the inhibitory effects of interferon  (IFN), the products of
certain IFN-inducible genes known to influence hematopoietic cell
survival were quantified. High constitutive expression of the
IFN-inducible genes, IFN-stimulated gene factor 3 gamma subunit (ISGF3), IFN regulatory factor-1 (IRF-1), and the cyclin-dependent kinase inhibitor p21WAF1 was found in
FANCC mutant B lymphoblasts, low-density bone marrow cells,
and murine embryonic fibroblasts. Paradoxically, these cells do not
activate signal transducer and activator of transcription (STAT) 1 properly. In an attempt to clarify mechanisms by which FA-C cells
overexpress IFN-inducible genes in the face of defective STAT1
phosphorylation, it was reasoned that decreased levels of activated
STAT1 might result in reduced expression of a hematopoietic IFN-responsive protein that normally modulates expression of other
IFN-responsive genes. Levels of the IFN-inducible factor IFN
consensus sequence binding protein (ICSBP), a negative trans-acting regulator of some IFN-inducible genes, were quantified. ICSBP levels
were reduced in FA-C B lymphoblasts and MEFs. However, enforced
expression of ICSBP failed to down-regulate IRF-1, ISGF3, and
p21WAF1. Thus, the FANCC protein functions to modulate
expression of a family of genes that in normal cells are inducible only
by specific environmental cues for apoptosis or mitogenic inhibition,
but it does so independently of the classic IFN-STAT1 pathway and is not the direct result of reduced ICSBP expression.
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