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Exp Hematol. 2016 Mar;44(3):161-5.e4. doi: 10.1016/j.exphem.2015.11.006. Epub 2015 Dec 1.

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

Author information

1
Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO.
2
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
3
Department of Genetics, Washington University School of Medicine, St. Louis, MO.
4
Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO. Electronic address: tomasson@dom.wustl.edu.

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.

PMID:
26607597
PMCID:
PMC4789175
[Available on 2017-03-01]
DOI:
10.1016/j.exphem.2015.11.006
[Indexed for MEDLINE]
Free PMC Article

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