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

Oncogene volume 21, pages 1600–1610 (2002)Cite this article

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 Faslpr/lpr (CD95 receptor mutant) and FasLgld/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.

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Acknowledgements

We thank Dr K Krishnaraju for assistance with the murine bone marrow cell culture analyses. This research was supported by National Institutes of Health grant R01CA81168 to B Hoffman.

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Authors and Affiliations

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

    Arshad Amanullah, Dan A Liebermann & Barbara Hoffman

  2. Department of Biochemistry, Temple University School of Medicine, 3307 N. Broad Street, Philadelphia, 19140, Pennsylvania, PA, USA

    Arshad Amanullah, Dan A Liebermann & Barbara Hoffman

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  1. Arshad Amanullah
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  2. Dan A Liebermann
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  3. Barbara Hoffman
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Correspondence to Dan A Liebermann or Barbara Hoffman.

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Amanullah, A., Liebermann, D. & Hoffman, B. Deregulated c-Myc prematurely recruits both Type I and II CD95/Fas apoptotic pathways associated with terminal myeloid differentiation. Oncogene 21, 1600–1610 (2002). https://doi.org/10.1038/sj.onc.1205231

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