Distinct B-Cell Specific Transcriptional Contexts of the BCL2 Oncogene Impact Pre-Malignant Development in Mouse Models

Abstract

Upregulated expression of the anti-apoptotic BCL2 oncogene is a common feature of various types of B-cell malignancies, from lymphoma to leukemia or myeloma. It is currently unclear how the various patterns of deregulation observed in pathology eventually impact the phenotype of malignant B cells and their microenvironment. Follicular lymphoma (FL) is the most common non-Hodgkin lymphoma arising from malignant germinal center (GC) B-cells, and its major hallmark is the t(14:18) translocation occurring in B cell progenitors and placing the BCL2 gene under the control of the immunoglobulin heavy chain locus regulatory region (IgH 3′RR), thus exposing it to constitutive expression and hypermutation. Translocation of BCL2 onto Ig light chain genes, BCL2 gene amplification, and other mechanisms yielding BCL2 over-expression are, in contrast, rare in FL and rather promote other types of B-cell lymphoma, leukemia, or multiple myeloma. In order to assess the impact of distinct BCL2 deregulation patterns on B-cell fate, two mouse models were designed that associated BCL2 and its full P1-P2 promoter region to either the IgH 3′RR, within a “3′RR-BCL2” transgene mimicking the situation seen in FL, or an Ig light chain locus context, through knock-in insertion at the Igκ locus (“Igκ-BCL2” model). While linkage to the IgH 3′ RR mostly yielded expression in GC B-cells, the Igκ-driven up-regulation culminated in plasmablasts and plasma cells, boosting the plasma cell in-flow and the accumulation of long-lived plasma cells. These data demonstrate that the timing and level of BCL2 deregulation are crucial for the behavior of B cells inside GC, an observation that could strongly impact the lymphomagenesis process triggered by secondary genetic hits.

Attempts to evaluate locus suicide recombination and its potential role in B cell negative selection in the mouse

“…Thus, functionally spliced chimeric transcripts are induced upon B cell activation in vitro. With the aim to improve the survival of hIgM + cells in vivo, we bred LSRµKI mice with BCL2 overexpressing mice (34) and quantified hIgM transcripts in white blood B cells 2 months after SRBC immunization: the amount of hIgM transcripts however remained similar in double mutant mice compared to LSRµKI mice. BCL2 overexpression thus did not significantly rescued B cells expressing hIgM in these conditions (Figure S1G).…”

Modeling the crosstalk between malignant B cells and their microenvironment in B-cell lymphomas: challenges and opportunities

“…Unfortunately, this model was not further characterized. More recently, another attempt to model FL-like BCL2 deregulation has been proposed (77). In this study, human BCL2 was introduced either by knock-in at the Igk locus, resulting in a pan-B cell deregulation, or as a transgene under the control of the 3'RR enhancer, resulting in induction of BCL2 expression in early GC B cells.…”