Multiple inhibitory cytokines induce deregulated progenitor growth and apoptosis in hematopoietic cells from Fac(-/-) mice

Laura S. Haneline, Hal E. Broxmeyer, Scott Cooper, Giao Hangoc, Madeleine Carreau, Manuel Buchwald, D. Wade Clapp

Research output: Contribution to journalArticle

143 Scopus citations

Abstract

We used a murine model containing a disruption of the murine homologue (Fac) of Fanconi Anemia group C (FAC) to evaluate the role of Fac in the pathogenesis of bone marrow (BM) failure. Methylcellulose cultures of BM cells from Fac(-/-) and Fac(+/+) mice were established to examine the growth of multipotent and lineage-restricted progenitors containing inhibitory cytokines, including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF- α), and macrophage inflammatory protein-1α (MIP-1α). Clonogenic growth of Fac(-/-) progenitors was reduced by 50% at 50- to 100-fold lower concentrations of all inhibitory cytokines evaluated. We hypothesized that the aberrant responsiveness to inhibitory cytokines in clonogenic cells may be a result of deregulated apoptosis. To test this hypothesis, we performed the TUNEL assay on purified populations of primary BM cells enriched for hematopoietic progenitors or differentiated myeloid cells. After stimulation with TNF-α, accentuated apoptosis was observed in both populations of Fac(- /-) cells. In addition, deregulated apoptosis was also noted in the most immature phenotypic population of hematopoietic cells after stimulation with MIP-lα. Together these data suggest a role of Fac in affecting the signaling of multiple cytokine pathways and support cytokine-mediated apoptosis as a major mechanism responsible for BM failure observed in FA patients.

Original languageEnglish (US)
Pages (from-to)4092-4098
Number of pages7
JournalBlood
Volume91
Issue number11
StatePublished - Jun 1 1998

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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