B Cell–specific Transgenic Expression of Bcl2 Rescues Early B Lymphopoiesis but Not B Cell Responses in BOB.1/OBF.1-deficient Mice

Abstract

Mice deficient for the transcriptional coactivator BOB.1/OBF.1 show several defects in B cell differentiation. Numbers of immature transitional B cells in the bone marrow are reduced and fewer B cells reach the periphery. Furthermore, germinal center B cells are absent and marginal zone (MZ) B lymphocytes are markedly reduced. Increased levels of B cell apoptosis in these mice prompted us to analyze expression and function of antiapoptotic proteins. Bcl2 expression is strongly reduced in BOB.1/OBF.1-deficient pre–B cells. When BOB.1/OBF.1-deficient mice were crossed with Bcl2-transgenic mice, B cell development in the bone marrow and numbers of B cells in peripheral lymphoid organs were normalized. However, neither germinal center B cells nor MZ B cells were rescued. Additionally, Bcl2 did not rescue the defects in signaling and affinity maturation found in BOB.1/OBF.1-deficient mice. Interestingly, Bcl2-transgenic mice by themselves show an MZ B cell defect. Virtually no functional MZ B cells were detected in these mice. In contrast, mice deficient for Bcl2 show a relative increase in MZ B cell numbers, indicating a previously undetected function of Bcl2 for this B cell compartment.

Oct transcription factors mediate t(14;18) lymphoma cell survival by directly regulating bcl-2 expression

“…However, Brunner et al (2003) did find that Bob À/À mice displayed reduced levels of bcl-2 mRNA and that Bcl-2 was capable of rescuing the early stages of B-cell development in those mice, although there was no indication of a direct link between Bob-1 and bcl-2 gene regulation. We found that Bob-1 was able to activate a reporter construct containing the bcl-2 regulatory region in malignant B cells.…”

“…Expression analysis studies with Bob-1-deficient B cells showed that Bob-1 targets genes responsible for B-cell proliferation and signaling (Kim et al, 2003). In addition, Brunner et al (2003) have shown that expression of the anti-apoptotic factor Bcl-2 is able to rescue early B lymphopoiesis, but not B-cell responsiveness in Bob-1-deficient mice. Although these studies indicate the importance of Bob-1 for mediating normal B-cell proliferation and survival signaling, the role of this factor and Oct-2 in malignant cells remains unclear.…”

The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6

“…Mice deficient for Bob1 show multiple defects in B‐cell development, do not form GCs, and consequently lack high‐affinity antibody‐secreting plasma cells (Kim et al , 1996; Schubart et al , 1996; Hess et al , 2001; Brunner et al , 2003; Corcoran et al , 2005). On the T‐cell side, the role of Bob1 remained largely enigmatic.…”

POU2AF1, an amplification target at 11q23, promotes growth of multiple myeloma cells by directly regulating expression of a B-cell maturation factor, TNFRSF17

“…However, they evaluated only the number of apoptotic cells, not total cell growth or the numbers of proliferative cells, after knockdown of those factors. Since studies with POU2AF1-deficient B cells have indicated that POU2AF1 targets genes are responsible for B-cell proliferation and signaling (Kim et al, 2003) and that expression of the antiapoptotic factor Bcl-2 in POU2AF1 À/À mice is able to rescue early B lymphopoiesis but not B-cell responsiveness (Brunner et al, 2003), a primary role of POU2AF1 and Oct elements might be to act as cell-growth and/or survival factors in normal and malignant development of B-cell lineages. Our experiments using stable transfectants expressing POU2AF1 and siRNA-induced knockdown of POU2AF1 in cell lines highly expressing the gene successfully demonstrated the growth-promoting effect of overexpressed POU2AF1 in human MM cells.…”

“…The candidate transcriptional targets for POU2AF1 included genes encoding BAFFR, TNFRSF17, Bcl-2, cyclin D3 and osteopontin (Samardzic et al, 2002;Brunner et al, 2003;Kim et al, 2003;Lins et al, 2003), proteins that might be Known genes were selected from the SRO of 11q23 amplicon in MM cell lines (Figure 2b). The expression level of each gene in each cell line was divided by the average value of that in KMM1 and KM-5 cell lines (reference value), which have normal copy numbers of 11q, after normalization with GAPDH, and recorded as a fold increase in relative expression level.…”