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

Abstract

Previously we have reported that deregulated expression of c-myc in normal and leukemic myeloid cells blocked di erentiation 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 di erentiation program. Analysis of the regulated components of this pathway revealed that IL6-mediated induction of di erentiation 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 signi®cantly suppressed relative to c-myc-transduced wild type bone marrow cells upon induction of di erentiation. These data indicate that c-myc-mediated apoptosis associated with blocks in myeloid di erentiation is dependent on the Fas/CD95 pathway. Our ®ndings o er important new insights into understanding how deregulated c-myc alters normal blood cell homeostasis, and how additional mutations might promote leukemogenesis.

The IKK2/NF-κB pathway suppresses MYC-induced lymphomagenesis

“…MYC has been shown to sensitize cells to Fas-induced death. 48 Insensitivity to Fas-mediated apoptosis is a common attribute of BL cells and correlates with low Fas surface expression. 49,50 Ramos and Namalwa cells are completely resistant to agonistic Fas-antibody and blocking canonical NF-B activation did not enhance sensitivity.…”

Fos modulates myeloid cell survival and differentiation and partially abrogates the c-Myc block in terminal myeloid differentiation

“…To the best of our knowledge, this is the first instance where Fos has been documented to modulate myeloid progenitor cell survival dependent on the availability of differentiation inducer. These observations suggest that Fos expression following physiologic stress, such as low levels of differentiation/ survival factors and/or following exposure of the organism to genotoxic stress, 3,20 is a safeguard that keeps myeloid cell homeostasis in check to prevent fixation of mutations that may promote leukemogenesis. While our work was in progress, AP-1 had been implicated in the regulation of proliferation and survival of erythroid cells as well, suggesting that different AP-1 factors may play distinct roles in triggering apoptosis (JunB) verses protection from apoptosis (c-Jun).…”

“…19 To determine if death receptor signaling contributes to Fos-mediated apoptosis in M1 myeloblasts, flow cytometry was used to determine if the Fas receptor is expressed in M1FosER cells, untreated or following activation of Fos. It was previously reported that M1 cells do not express Fas receptors 20 ; similarly, M1FosER cells, untreated or treated with ␤E2, do not express Fas receptors (data not shown), indicating that the Fas/CD95 pathway is not involved in c-Fosmediated apoptosis. Caspase-8 is the initiator caspase not only in the Fas/CD95 pathway but also in other related death receptor (ie, TNFa/TNFR) pathways.…”

p53 is a regulator of macrophage differentiation

“…A detailed analysis demonstrated that c-myc induces apoptosis in IL-6-treated myeloid cells through the CD95/Fas pathway. 61 The Fas pathway was also implicated as a mechanism for p53-mediated apoptosis that is transcription-independent. 62 Therefore, it would be interesting to examine whether this mechanism underlies the induction of apoptosis by the p53 (22)(23) protein, upon exposure to IL-6.…”