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

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

Research output: Contribution to journalArticle

142 Citations (Scopus)

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

Fingerprint

Apoptosis
Cytokines
Bone
Growth
Bone Marrow Cells
Tumor Necrosis Factor-alpha
Bone Marrow
Population
Fanconi Anemia
Macrophage Inflammatory Proteins
Methylcellulose
In Situ Nick-End Labeling
Myeloid Cells
Interferons
Assays
Cells

ASJC Scopus subject areas

  • Hematology

Cite this

Multiple inhibitory cytokines induce deregulated progenitor growth and apoptosis in hematopoietic cells from Fac(-/-) mice. / Haneline, Laura; Broxmeyer, Hal; Cooper, Scott; Hangoc, Giao; Carreau, Madeleine; Buchwald, Manuel; Clapp, D.

In: Blood, Vol. 91, No. 11, 01.06.1998, p. 4092-4098.

Research output: Contribution to journalArticle

Haneline, Laura ; Broxmeyer, Hal ; Cooper, Scott ; Hangoc, Giao ; Carreau, Madeleine ; Buchwald, Manuel ; Clapp, D. / Multiple inhibitory cytokines induce deregulated progenitor growth and apoptosis in hematopoietic cells from Fac(-/-) mice. In: Blood. 1998 ; Vol. 91, No. 11. pp. 4092-4098.
@article{c56f12d2d3fc4339aac7f7ebd715e459,
title = "Multiple inhibitory cytokines induce deregulated progenitor growth and apoptosis in hematopoietic cells from Fac(-/-) mice",
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.",
author = "Laura Haneline and Hal Broxmeyer and Scott Cooper and Giao Hangoc and Madeleine Carreau and Manuel Buchwald and D. Clapp",
year = "1998",
month = "6",
day = "1",
language = "English",
volume = "91",
pages = "4092--4098",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "11",

}

TY - JOUR

T1 - Multiple inhibitory cytokines induce deregulated progenitor growth and apoptosis in hematopoietic cells from Fac(-/-) mice

AU - Haneline, Laura

AU - Broxmeyer, Hal

AU - Cooper, Scott

AU - Hangoc, Giao

AU - Carreau, Madeleine

AU - Buchwald, Manuel

AU - Clapp, D.

PY - 1998/6/1

Y1 - 1998/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0032101030&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032101030&partnerID=8YFLogxK

M3 - Article

VL - 91

SP - 4092

EP - 4098

JO - Blood

JF - Blood

SN - 0006-4971

IS - 11

ER -