Reversal of Blimp-1-mediated apoptosis by A1, a member of the Bcl-2 family

Abstract

Blimp‐1 (B lymphocyte‐induced maturation protein 1) is strongly expressed during the late stages of B cell differentiation to immunoglobulin‐secreting plasma cells. Overexpression of Blimp‐1 in B lymphoma cells has been reported to induce either growth arrest and cell death or Ig secretion and terminal differentiation, depending on the developmental stage of the recipient lymphomas. By using a retroviral expression system we show that Blimp‐1‐transduced immature WEHI 231 murine B lymphoma cells produce J chain, increased levels of the secretory form of μ heavy chain mRNA and secrete IgM for a short period of time. Concomitantly, they exhibit altered ratios of c‐myc/mad4 mRNA levels, a reduction in the expression of the anti‐apoptotic bcl‐2 family member A1 and a distinct growth disadvantage, followed by cell death. Reintroduction of A1 by retroviral transduction greatly extends the life span of Blimp‐1‐expressing WEHI 231 cells which continue to secrete IgM. These data suggest that levels of A1 may determine the checkpoint between death and survival of Blimp‐1‐expressing B cells at different stages of differentiation.

Ligation of CD27 on Murine B Cells Responding to T-Dependent and T-Independent Stimuli Inhibits the Generation of Plasma Cells

“…6). Because these gene products are specifically expressed in cells that have committed to Ig secretion (42)(43)(44)(45), our results suggest that CD27 engagement prevents the differentiation of activated B cells into plasma cells. Signals that are responsible for commitment to the plasma cell lineage have not been unambiguously identified, although some candidate molecules have been reported.…”

Altered mRNA expression of Pax5 and Blimp-1 in B cells in multiple myeloma

“…14,17 Blimp-1 also regulates several target genes, including transcription factor c-myc, antiapoptotic bcl-2 family member A1, syndecan-1, and J chain. 30,53,54 We compared levels of full-length Pax5 expression in CD22 ϩ and CD22 Ϫ cells from MM patients to levels of Blimp-1 expression. A clear inverse correlation in the expression levels was observed in 7 of 8 comparisons.…”

“…30 It follows that if Blimp-1 were prematurely expressed in a B-cell population, A1 expression could be repressed. We investigated A1 expression in B cell-enriched populations from MM patients and healthy subjects by semiquantitative RT-PCR ( Figure 10A).…”

BLIMP1α, the master regulator of plasma cell differentiation is a tumor supressor gene in B cell lymphomas

“…The e xpression of BLIMP1 in B cell lymphomas representative of immature or partially activated B cells induces cell cycle arrest and apoptosis, in part by repressing the expression of C-MYC and of the anti-apoptotic BCL2 family member A1 (BCL2A1). In contrast, in fully activated B cells BLIMP1 expression promotes differentiation 28,46 . This has led to suggestion that BLIMP1 expression induces growth arrest and cell death at earlier stages of B cell development but promotes maturation and Ig secretion at later stages of B cell differentiation.…”