Deletion of Rb1 induces both hyperproliferation and cell death in murine germinal center B cells

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-gamma-1-Cre (C gamma 1) mice expressing the Cre recombinase in class-switched B cells in a p107(-/-) background to prevent p107 from compensating for Rb1 loss (C gamma 1-Rb1(F/F)-p107(-/-)). All mice developed normally, but B cells with two copies of Rb1 deleted (C gamma 1-Rb1(F/F)-p107(-/-)) exhibited increased proliferation and cell death compared with C gamma 1-Rb1(+/+)p107(-/-)controls ex vivo. In vivo, C gamma 1-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 Rbl 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 Rbl loss is not sufficient to transform post-germinal center B cells and that additional, specific mutations are likely required to cooperate with Rbl loss to induce malignant transformation. Copyright (C) 2016 ISEH-International Society for Experimental Hematology. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).