MIF loss impairs Myc-induced lymphomagenesis.
Macrophage migration inhibitory factor (MIF) is a potent regulator of inflammation and cell growth. Using the Emu-Myc lymphoma mouse model, we demonstrate that loss of MIF markedly delays the onset of B-cell lymphoma development in vivo. The molecular basis for this MIF-loss-induced phenotype is the perturbed DNA-binding activity of E2F factors and the concomitantly enhanced tumor suppressor activity of the p53 pathway. Accordingly, premalignant MIF-null Emu-Myc B-cells are predisposed to delayed S-phase progression and increased apoptosis. MIF-deficient lymphomas that do arise under these conditions contain frequent ARF deletions and p53 inactivating mutations. Conversely, MIF expression is retained in tumors developed by wild-type Emu-Myc animals, and the presence of one or both MIF alleles is sufficient to accelerate the development of Myc-induced lymphomas. Collectively, these results indicate that MIF promotes Myc-mediated tumorigenesis, at least in the B-lymphoid compartment, and implicate MIF as a mediator of malignant cell growth in vivo.
Talos
F
F
Department of Pathology, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
Mena
P
P
Fingerle-Rowson
G
G
Moll
U
U
Petrenko
O
O
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D050684:E2F Transcription Factors; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D016259:Genes, myc / Q000235:genetics; D020287:In Situ Nick-End Labeling; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D008263:Macrophage Migration-Inhibitory Factors; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53