Format

Send to

Choose Destination
See comment in PubMed Commons below
Oncogene. 2002 Feb 28;21(10):1600-10.

Deregulated c-Myc prematurely recruits both Type I and II CD95/Fas apoptotic pathways associated with terminal myeloid differentiation.

Author information

  • 1Fels Institute for Cancer Research, Temple University School of Medicine, 3307 N. Broad Street, Philadelphia, Pennsylvania, PA 19140, USA.

Abstract

Previously we have reported that deregulated expression of c-myc in normal and leukemic myeloid cells blocked differentiation and, concomitantly, induced p53-independent apoptosis. Here, we show that this morbidity was due to premature recruitment of the Fas/CD95 cell death pathway which normally operates to induce apoptosis at the end of the terminal myeloid differentiation program. Analysis of the regulated components of this pathway revealed that IL6-mediated induction of differentiation resulted in rapid cell surface expression of CD95 receptor. Deregulated c-myc prevented the downregulation of CD95 ligand by maintaining its transcription, but caused premature downregulation of c-FLIP. First, the Type II (mitochondria-dependent, bcl-2-sensitive) and, then, the Type I (mitochondria-independent, bcl-2-insensitive) pathway were activated. Stable exogenous c-FLIP expression completely rescued the apoptotic phenotype. Furthermore, when the deregulated c-myc transgene was stably transduced into bone marrow cells from Fas(lpr/lpr) (CD95 receptor mutant) and FasL(gld/gld) (CD95 ligand mutant) mice, cell death was significantly suppressed relative to c-myc-transduced wild type bone marrow cells upon induction of differentiation. These data indicate that c-myc-mediated apoptosis associated with blocks in myeloid differentiation is dependent on the Fas/CD95 pathway. Our findings offer important new insights into understanding how deregulated c-myc alters normal blood cell homeostasis, and how additional mutations might promote leukemogenesis.

PMID:
11896589
DOI:
10.1038/sj.onc.1205231
[PubMed - indexed for MEDLINE]
Free full text
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group
    Loading ...
    Support Center