Inactivation of the Fanconi anemia group C gene augments interferon-γ- induced apoptotic responses in hematopoietic cells

R. Keaney Rathbun, Gregory R. Faulkner, Marika H. Ostroski, Tracy A. Christianson, Grant Hughes, Gary Jones, Robert Cahn, Richard Maziarz, Gordon Royle, Winifred Keeble, Michael Heinrich, Markus Grompe, Paula A. Tower, Grover C. Bagby

Research output: Contribution to journalArticle

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Abstract

Hematopoietic progenitor cells (HPC) from mice nullizygous at the Fanconi anemia (FA) group C locus (FAC -/-) are hypersensitive to the mitotic inhibitory effects of interferon (IFN-γ). We tested the hypothesis that HPC from the bone marrow of Fanconi group C children are similarly hypersensitive and that the fags pathway is involved in affecting programmed cell death in response to low doses of IFN-γ. In normal human and murine HPC, IFN-γ primed the fags pathway and induced both fags and interferon response factor- 1 (IRF-1) gene expression. These IFN-γ-induced apoptotic responses in HPC from the marrow of a child with FA of the C group (FA-C) and in FAC -/- mice occurred at significantly lower IFN doses (by an order of magnitude) than did the apoptotic responses of normal HPC. Treatment of FA-C CD34+ cells with low doses of recombinant IFN-γ, inhibited growth of colony forming unit granulocyte-macrophage and burst-forming unit erythroid, while treatment with blocking antibodies to fags augmented clonal growth and abrogated the clonal inhibitory effect of IFN-γ. Transfer of the normal FAC gene into FA-C B- cell lines prevented mitomycin C-induced apoptosis, but did not suppress fags expression or inhibit the primed fags pathway. However, the kinetics of Stat1-phosphate decay in IFN-γ-treated cells was prolonged in mutant cells and was normalized by transduction of the normal FAC gene. Therefore, the normal FAC protein serves, in part, to modulate IFN-γ signals. HPC bearing inactivating mutations of FAC fail to normally modulate IFN-γ signals and, as a result, undergo apoptosis executed through the fags pathway.

Original languageEnglish (US)
Pages (from-to)974-985
Number of pages12
JournalBlood
Volume90
Issue number3
StatePublished - Aug 1 1997
Externally publishedYes

Fingerprint

Fanconi Anemia
Interferons
Genes
Hematopoietic Stem Cells
Bearings (structural)
Bone Marrow
Cells
Apoptosis
Granulocyte-Macrophage Progenitor Cells
Erythroid Precursor Cells
Blocking Antibodies
Macrophages
Mitomycin
Cell death
Growth
Gene expression
Bone
B-Lymphocytes
Cell Death
Phosphates

ASJC Scopus subject areas

  • Hematology

Cite this

Rathbun, R. K., Faulkner, G. R., Ostroski, M. H., Christianson, T. A., Hughes, G., Jones, G., ... Bagby, G. C. (1997). Inactivation of the Fanconi anemia group C gene augments interferon-γ- induced apoptotic responses in hematopoietic cells. Blood, 90(3), 974-985.

Inactivation of the Fanconi anemia group C gene augments interferon-γ- induced apoptotic responses in hematopoietic cells. / Rathbun, R. Keaney; Faulkner, Gregory R.; Ostroski, Marika H.; Christianson, Tracy A.; Hughes, Grant; Jones, Gary; Cahn, Robert; Maziarz, Richard; Royle, Gordon; Keeble, Winifred; Heinrich, Michael; Grompe, Markus; Tower, Paula A.; Bagby, Grover C.

In: Blood, Vol. 90, No. 3, 01.08.1997, p. 974-985.

Research output: Contribution to journalArticle

Rathbun, RK, Faulkner, GR, Ostroski, MH, Christianson, TA, Hughes, G, Jones, G, Cahn, R, Maziarz, R, Royle, G, Keeble, W, Heinrich, M, Grompe, M, Tower, PA & Bagby, GC 1997, 'Inactivation of the Fanconi anemia group C gene augments interferon-γ- induced apoptotic responses in hematopoietic cells', Blood, vol. 90, no. 3, pp. 974-985.
Rathbun RK, Faulkner GR, Ostroski MH, Christianson TA, Hughes G, Jones G et al. Inactivation of the Fanconi anemia group C gene augments interferon-γ- induced apoptotic responses in hematopoietic cells. Blood. 1997 Aug 1;90(3):974-985.
Rathbun, R. Keaney ; Faulkner, Gregory R. ; Ostroski, Marika H. ; Christianson, Tracy A. ; Hughes, Grant ; Jones, Gary ; Cahn, Robert ; Maziarz, Richard ; Royle, Gordon ; Keeble, Winifred ; Heinrich, Michael ; Grompe, Markus ; Tower, Paula A. ; Bagby, Grover C. / Inactivation of the Fanconi anemia group C gene augments interferon-γ- induced apoptotic responses in hematopoietic cells. In: Blood. 1997 ; Vol. 90, No. 3. pp. 974-985.
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abstract = "Hematopoietic progenitor cells (HPC) from mice nullizygous at the Fanconi anemia (FA) group C locus (FAC -/-) are hypersensitive to the mitotic inhibitory effects of interferon (IFN-γ). We tested the hypothesis that HPC from the bone marrow of Fanconi group C children are similarly hypersensitive and that the fags pathway is involved in affecting programmed cell death in response to low doses of IFN-γ. In normal human and murine HPC, IFN-γ primed the fags pathway and induced both fags and interferon response factor- 1 (IRF-1) gene expression. These IFN-γ-induced apoptotic responses in HPC from the marrow of a child with FA of the C group (FA-C) and in FAC -/- mice occurred at significantly lower IFN doses (by an order of magnitude) than did the apoptotic responses of normal HPC. Treatment of FA-C CD34+ cells with low doses of recombinant IFN-γ, inhibited growth of colony forming unit granulocyte-macrophage and burst-forming unit erythroid, while treatment with blocking antibodies to fags augmented clonal growth and abrogated the clonal inhibitory effect of IFN-γ. Transfer of the normal FAC gene into FA-C B- cell lines prevented mitomycin C-induced apoptosis, but did not suppress fags expression or inhibit the primed fags pathway. However, the kinetics of Stat1-phosphate decay in IFN-γ-treated cells was prolonged in mutant cells and was normalized by transduction of the normal FAC gene. Therefore, the normal FAC protein serves, in part, to modulate IFN-γ signals. HPC bearing inactivating mutations of FAC fail to normally modulate IFN-γ signals and, as a result, undergo apoptosis executed through the fags pathway.",
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AU - Rathbun, R. Keaney

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AU - Christianson, Tracy A.

AU - Hughes, Grant

AU - Jones, Gary

AU - Cahn, Robert

AU - Maziarz, Richard

AU - Royle, Gordon

AU - Keeble, Winifred

AU - Heinrich, Michael

AU - Grompe, Markus

AU - Tower, Paula A.

AU - Bagby, Grover C.

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N2 - Hematopoietic progenitor cells (HPC) from mice nullizygous at the Fanconi anemia (FA) group C locus (FAC -/-) are hypersensitive to the mitotic inhibitory effects of interferon (IFN-γ). We tested the hypothesis that HPC from the bone marrow of Fanconi group C children are similarly hypersensitive and that the fags pathway is involved in affecting programmed cell death in response to low doses of IFN-γ. In normal human and murine HPC, IFN-γ primed the fags pathway and induced both fags and interferon response factor- 1 (IRF-1) gene expression. These IFN-γ-induced apoptotic responses in HPC from the marrow of a child with FA of the C group (FA-C) and in FAC -/- mice occurred at significantly lower IFN doses (by an order of magnitude) than did the apoptotic responses of normal HPC. Treatment of FA-C CD34+ cells with low doses of recombinant IFN-γ, inhibited growth of colony forming unit granulocyte-macrophage and burst-forming unit erythroid, while treatment with blocking antibodies to fags augmented clonal growth and abrogated the clonal inhibitory effect of IFN-γ. Transfer of the normal FAC gene into FA-C B- cell lines prevented mitomycin C-induced apoptosis, but did not suppress fags expression or inhibit the primed fags pathway. However, the kinetics of Stat1-phosphate decay in IFN-γ-treated cells was prolonged in mutant cells and was normalized by transduction of the normal FAC gene. Therefore, the normal FAC protein serves, in part, to modulate IFN-γ signals. HPC bearing inactivating mutations of FAC fail to normally modulate IFN-γ signals and, as a result, undergo apoptosis executed through the fags pathway.

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