title: Critical B-lymphoid cell intrinsic role of endogenous MCL-1 in c-MYC-induced lymphomagenesis.
abstract: Evasion of apoptosis is critical for tumorigenesis, and sustained survival of nascent neoplastic cells may depend upon the endogenous levels of pro-survival BCL-2 family members. Indeed, previous studies using gene-targeted mice revealed that BCL-XL, but surprisingly not BCL-2, is critical for the development of c-MYC-induced pre-B/B lymphomas. However, it remains unclear whether another pro-survival BCL-2 relative contributes to their development. MCL-1 is an intriguing candidate, because it is required for cell survival during early B-lymphocyte differentiation. It is expressed abnormally high in several types of human B-cell lymphomas and is implicated in their resistance to chemotherapy. To test the B-cell intrinsic requirement for endogenous MCL-1 in lymphoma development, we conditionally deleted Mcl-1 in B-lymphoid cells of Eμ-Myc transgenic mice. We found that MCL-1 loss in early B-lymphoid progenitors delayed MYC-driven lymphomagenesis. Moreover, the lymphomas that arose when MCL-1 levels were diminished appeared to have been selected for reduced levels of BIM and/or increased levels of BCL-XL. These results underscore the importance of MCL-1 in lymphoma development and show that alterations in the levels of other cell death regulators can compensate for deficiencies in MCL-1 expression.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: S
authors.identifier: http://orcid.org/0000-0003-0467-7871
authors.initials: S
authors.lastname: Grabow
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: G L
authors.initials: GL
authors.lastname: Kelly
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: A R D
authors.initials: AR
authors.lastname: Delbridge
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: P N
authors.initials: PN
authors.lastname: Kelly
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Bouillet
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: J M
authors.initials: JM
authors.lastname: Adams
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Strasser
mesh_terms: D000818:Animals; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*
chemical_list: C579094:Mcl1 protein, mouse; C489428:Myc protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016271:Proto-Oncogene Proteins c-myc