Deregulated c-Myc prematurely recruits both Type I and II CD95/Fas apoptotic pathways associated with terminal myeloid differentiation.
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.
Amanullah
Arshad
A
Fels Institute for Cancer Research, Temple University School of Medicine, 3307 N. Broad Street, Philadelphia, Pennsylvania, PA 19140, USA.
Liebermann
Dan A
DA
Hoffman
Barbara
B
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009154:Mutation; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; C506387:Cflar protein, mouse; C505534:Fadd protein, mouse; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; C505658:Fasl protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D019014:fas Receptor; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases