Deregulated Bcl-2-immunoglobulin transgene expands a resting but responsive immunoglobulin M and D-expressing B-cell population.

Abstract

We characterized the basis for the follicular lymphoproliferation in transgenic mice bearing a Bcl-2-immunoglobulin (Bcl-2-Ig) minigene representing the t(14;18) of human follicular lymphoma. Discriminatory S1 nuclease protection assays revealed that the Bcl-2-Ig transgene was overexpressed relative to endogenous mouse Bcl-2 in spleen and thymus. Western (immunoblot) Specific types of chromosomal translocations are highly associated with distinct malignant diseases. Previously identified proto-oncogenes were shown to flank several of these breakpoints and were either fused to other genes, e.g., bcr-abl (26), or deregulated as with myc (2,7,27). These models suggested that examination of other recurrent translocations would reveal new proto-oncogenes at their breakpoints. The t(14;18)(q32;q21) of follicular B-cell lymphoma has provided one such opportunity. The molecular cloning of the derivative 14 breakpoint (1, 3, 28) led to the identification of the putative proto-oncogene Bcl-2 at 18q21. The translocation juxtaposed Bcl-2 with the immunoglobulin locus, resulting in inappropriately elevated levels of a Bcl-2-immunoglobulin (Bcl-2-Ig) fusion RNA for the mature stage of these follicular B-cell tumors (4,10,25 S1 nuclease protection assay.

t(14;18), a journey to eternity

“…Splenic B cells have a prolonged lifespan, but in vitro activation seems unaffected. 67,68 Another Bcl-2 transgenic mice model demonstrates increased B cell numbers of all developmental stages without evidence of follicular hyperplasia, 69 and probably reflects differences in the genetic background or bcl-2 expression cassette in both transgenic lines. Bcl-2 overexpression in the B cell lineage prolongs antibody responses upon antigenic challenge, 69 and prolongs B cell memory.…”

“…As a consequence of the BAX G67R mutation, a positive charged Arginine residue is introduced in the hydrophobic site of the BH3 domain. Both neighboring residues, lle 66 and Asp 68 , are involved in the binding of BAK to BCL-X L . 101 The G67R mutation may interfere with interactions of these residues with the hydrophobic pocket of BCL2 or BCL-X L .…”

BCL-2 in the crosshairs: tipping the balance of life and death

“…[6][7][8] Transgenic mice bearing a BCL-2-Ig minigene initially displayed a polyclonal follicular lymphoproliferation that selectively expanded a small resting IgM/IgD B-cell population. 4,9 These recirculating B cells accumulated because of an extended survival rather than increased proliferation. Despite a fourfold increase in resting B cell counts, BCL-2-Ig mice were initially quite healthy.…”

Bcl-2 reduces lymphomagenesis in ΔV-TCRβ transgenic mice

“…In addition, T-cell di erentiation is arrested at the CD4 + ;CD8 + ;CD3 dull stage although a small percentage of the thymocytes do mature to single positive T cells with high CD3 expression (Krimpenfort et al, 1989;Figure 2a and b). In bcl-2-Ig transgenic mice the surface phenotype of the thymus is not a ected (McDonnell et al, 1989(McDonnell et al, , 1990) although the transgene is functionally expressed (Brady et al, 1996a). In bitransgenic males the same was observed as seen in DV-TCRb males.…”

“…Bcl-2 collaborates with other oncogenes in lymphomagenesis (Strasser et al, 1990;Acton et al, 1992), supposedly by prolonging the longevity of preneoplastic lymphocytes (McDonnell et al, 1989(McDonnell et al, , 1990Strasser et al, 1991) thereby increasing the chance of accumulation of additional oncogenic events. DV-TCRb transgenic mice are highly predisposed to pre-T-cell lymphomas.…”