TY - JOUR
T1 - Deletion of Rb1 induces both hyperproliferation and cell death in murine germinal center B cells
AU - He, Zhiwen
AU - O'Neal, Julie
AU - Wilson, William C.
AU - Mahajan, Nitin
AU - Luo, Jun
AU - Wang, Yinan
AU - Su, Mack Y.
AU - Lu, Lan
AU - Skeath, James B.
AU - Bhattacharya, Deepta
AU - Tomasson, Michael H.
N1 - Funding Information:
This work was supported by the Barnes Hospital Foundation (MHT) and NIH Grant R01 CA175349 (MHT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.
Publisher Copyright:
© 2016 ISEH - International Society for Experimental Hematology.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - 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 Rb1Flox/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-Rb1F/F-p107-/-). All mice developed normally, but B cells with two copies of Rb1 deleted (Cγ1-Rb1F/F-p107-/-) exhibited increased proliferation and cell death compared with Cγ1-Rb1+/+-p107-/- controls ex vivo. In vivo, Cγ1-Rb1F/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.
AB - 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 Rb1Flox/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-Rb1F/F-p107-/-). All mice developed normally, but B cells with two copies of Rb1 deleted (Cγ1-Rb1F/F-p107-/-) exhibited increased proliferation and cell death compared with Cγ1-Rb1+/+-p107-/- controls ex vivo. In vivo, Cγ1-Rb1F/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.
UR - http://www.scopus.com/inward/record.url?scp=84960104044&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2015.11.006
DO - 10.1016/j.exphem.2015.11.006
M3 - Article
C2 - 26607597
AN - SCOPUS:84960104044
SN - 0301-472X
VL - 44
SP - 161-165.e4
JO - Experimental Hematology
JF - Experimental Hematology
IS - 3
ER -