title: Functional antagonism between pro-apoptotic BIM and anti-apoptotic BCL-XL in MYC-induced lymphomagenesis.
abstract: Genomic analyses revealed that many cancers have acquired abnormalities in their expression of pro- or anti-apoptotic members of the BCL-2 protein family. It is, however, unknown whether changes in pro- or anti-apoptotic BCL-2 family members have similar impact on tumorigenesis or whether changes in one subgroup have disproportionate impact. We compared the consequences of concomitant loss of anti-apoptotic Bclx and pro-apoptotic Bim on MYC-induced lymphomagenesis. Whereas only loss of both Bclx alleles markedly forestalled tumorigenesis, loss of a single Bim allele overcame this blockade. Conversely, loss of even a single Bim allele sufficed to substantially accelerate lymphomagenesis, and only loss of both but not loss of a single allele of Bclx could attenuate this acceleration. The evidence that modest (two-fold) monoallelic changes in the expression of at least some BH3-only proteins can profoundly impact tumorigenesis suggests that such aberrations, imposed by epigenetic or genetic changes, may expedite tumorigenesis more effectively than elevated expression of pro-survival BCL-2 family members. These findings further our understanding of the mechanisms of lymphomagenesis and possibly also cancer therapy.
authors.affiliation: 1] Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: A R D
authors.initials: AR
authors.lastname: Delbridge
authors.affiliation: 1] Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Grabow
authors.affiliation: 1] Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Bouillet
authors.affiliation: 1] Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: J M
authors.initials: JM
authors.lastname: Adams
authors.affiliation: 1] Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Strasser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D008223:Lymphoma / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C494812:Bcl2l1 protein, mouse; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; C489428:Myc protein, mouse; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D051020:bcl-X Protein