Loss of the Nf1 Tumor Suppressor Gene Decreases Fas Antigen Expression in Myeloid Cells

Kelly Hiatt, David Ingram, Hannah Huddleston, Dan Spandau, Reuben Kapur, D. Clapp

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Genetic loss of surface Fas antigen expression leads to reduced apoptosis of myeloid and lymphoid progenitor cells, and a propensity to develop autoimmunity and myeloid leukemia in mouse models. Oncogenic p21ras decreases surface Fas antigen expression and renders fibroblasts resistant to Fas mediated apoptosis. Neurofibromin, which is encoded by NF1, is a GTPase activating protein that negatively regulates p21ras activity. NF1 loss leads to deregulation of p21ras-effector pathways, which control myeloid cell survival Heterozygous inactivation of Nf1 increases mast cell numbers in Nf1 +/- mice, and enhances mast cell survival in response to c-kit ligand (kit-L). Here, we show that Nf1-deficient mast cells have reduced surface Fas antigen expression in response to kit-L and are resistant to Fas ligand-mediated apoptosis. Using genetic intercrosses between Nf1 +/- and class I A-PI-3K-deficient mice, we demonstrate that hyperactivation of the p21ras-class IA PI-3K pathway is the mechanism for this phenotype. Finally, we demonstrate that mast cells from both Fas antigen-deficient mice and Nf1 +/- mice are resistant to apoptosis following kit-L withdrawal in vivo. Thus, therapies designed to decrease p21 ras activity and up-regulate Fas antigen expression may limit the pathological accumulation of myeloid cells in disease states where p21 ras is hyperactivated.

Original languageEnglish
Pages (from-to)1471-1479
Number of pages9
JournalAmerican Journal of Pathology
Volume164
Issue number4
StatePublished - Apr 2004

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CD95 Antigens
Myeloid Cells
Tumor Suppressor Genes
Mast Cells
Stem Cell Factor
Surface Antigens
Apoptosis
Proto-Oncogene Proteins p21(ras)
Phosphatidylinositol 3-Kinases
Cell Survival
Lymphoid Progenitor Cells
Neurofibromin 1
Myeloid Progenitor Cells
GTPase-Activating Proteins
Myeloid Leukemia
Fas Ligand Protein
Autoimmunity
Up-Regulation
Fibroblasts
Cell Count

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Loss of the Nf1 Tumor Suppressor Gene Decreases Fas Antigen Expression in Myeloid Cells. / Hiatt, Kelly; Ingram, David; Huddleston, Hannah; Spandau, Dan; Kapur, Reuben; Clapp, D.

In: American Journal of Pathology, Vol. 164, No. 4, 04.2004, p. 1471-1479.

Research output: Contribution to journalArticle

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