title: Deletion of Rb1 induces both hyperproliferation and cell death in murine germinal center B cells.
abstract: The retinoblastoma gene (RB1) has been implicated as a tumor suppressor in multiple myeloma (MM), yet its role remains unclear because in the majority of cases with 13q14 deletions, un-mutated RB1 remains expressed from the retained allele. To explore the role of Rb1 in MM, we examined the functional consequences of single- and double-copy Rb1 loss in germinal center B cells, the cells of origin of MM. We generated mice without Rb1 function in germinal center B cells by crossing Rb1(Flox/Flox) with C-γ-1-Cre (Cγ1) mice expressing the Cre recombinase in class-switched B cells in a p107(-/-) background to prevent p107 from compensating for Rb1 loss (Cγ1-Rb1(F/F)-p107(-/-)). All mice developed normally, but B cells with two copies of Rb1 deleted (Cγ1-Rb1(F/F)-p107(-/-)) exhibited increased proliferation and cell death compared with Cγ1-Rb1(+/+)-p107(-/-) controls ex vivo. In vivo, Cγ1-Rb1(F/F)-p107(-/-) mice had a lower percentage of splenic B220+ cells and reduced numbers of bone marrow antigen-specific secreting cells compared with control mice. Our data indicate that Rb1 loss induces both cell proliferation and death in germinal center B cells. Because no B-cell malignancies developed after 1 year of observation, our data also suggest that Rb1 loss is not sufficient to transform post-germinal center B cells and that additional, specific mutations are likely required to cooperate with Rb1 loss to induce malignant transformation.
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Julie
authors.initials: J
authors.lastname: O'Neal
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO.
authors.forename: William C
authors.initials: WC
authors.lastname: Wilson
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Nitin
authors.initials: N
authors.lastname: Mahajan
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Jun
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Mack Y
authors.initials: MY
authors.lastname: Su
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Lan
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MO.
authors.forename: James B
authors.initials: JB
authors.lastname: Skeath
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Deepta
authors.initials: D
authors.lastname: Bhattacharya
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO. Electronic address: tomasson@dom.wustl.edu.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Tomasson
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018858:Germinal Center / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D016160:Retinoblastoma Protein / Q000172:deficiency*
chemical_list: D016160:Retinoblastoma Protein