title: Loss of a Single Mcl-1 Allele Inhibits MYC-Driven Lymphomagenesis by Sensitizing Pro-B Cells to Apoptosis.
abstract: MCL-1 is critical for progenitor cell survival during emergency hematopoiesis, but its role in sustaining cells undergoing transformation and in lymphomagenesis is only poorly understood. We investigated the importance of MCL-1 in the survival of B lymphoid progenitors undergoing MYC-driven transformation and its functional interactions with pro-apoptotic BIM and PUMA and the tumor suppressor p53 in lymphoma development. Loss of one Mcl-1 allele almost abrogated MYC-driven-lymphoma development owing to a reduction in lymphoma initiating pre-B cells. Although loss of the p53 target PUMA had minor impact, loss of one p53 allele substantially accelerated lymphoma development when MCL-1 was limiting, most likely because p53 loss also causes defects in non-apoptotic tumor suppressive processes. Remarkably, loss of BIM restored the survival of lymphoma initiating cells and rate of tumor development. Thus, MCL-1 has a major role in lymphoma initiating pro-B cells to oppose BIM, which is upregulated in response to oncogenic stress.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; The Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia. Electronic address: grabow@wehi.edu.au.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grabow
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; The Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Alex R D
authors.initials: AR
authors.lastname: Delbridge
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; The Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia; Department of Clinical Haematology and Bone Marrow Transplant Service, the Royal Melbourne Hospital, Melbourne, VIC 3050, Australia.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Aubrey
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; The Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Cassandra J
authors.initials: CJ
authors.lastname: Vandenberg
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; The Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia. Electronic address: strasser@wehi.edu.au.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D005838:Genotype; D053208:Kaplan-Meier Estimate; D008223:Lymphoma / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C488588:PUMA protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins
keywords: BIM; MCL-1; MYC; apoptosis; lymphoma; p53