IL-6 and Tumor Susceptibility Alleles of Strain BALB/C Cause Phenotypic Shift of MYC-Driven Lymphomas in Mice from Diffuse Large B-Cell Lymphoma (DLBCL) to Plasmacytoma (PCT)

Aims: Deregulation of cellular oncoprotein MYC (c-Myc) and the plasma cell growth, differentiation and survival cytokine, interleukin-6 (IL-6), are key pathogenetic factors in human high grade B-cell lymphomas (Burkitt lymphoma and DLBCL) and PCT respectively. Genomic instability, as a consequence of this deregulation, is poorly understood. Transgenic expression of these factors in the B-cell lineage, in mice, generates a pre-clinical model system of great relevance for human B-cell lymphoma counterparts. In this study we evaluated for the incidence of lymphomas in transgenic mouse models, with deregulated CMYC and IL-6. We performed a morphologic classification and correlation of the malignant lymphoid proliferations with the underlying genetic lesions.

Materials & Methods: Deregulation of CMYC was observed in gene-targeted C57BL/6 mice that harbor a His₆-tagged mouse Myc cDNA gene in themouse immunoglobulin heavy-chain locus (B6.iMyc mice). A double transgenic mouse model, using BALB/c mice, carry the same gene insertion, in addition to a widely expressed human IL-6 transgene (C.iMyc/IL-6 mice). Tumor tissue from the mice was processed by formalin fixation and embedded in paraffin. Sections from the paraffin blocks were stained with hematoxylin and eosin and evaluated for morphology. The morphologic evaluation of the lymphomas was performed blind to the genetic make up of the host, followed by genetic correlation with morphology.

Results: B6.iMyc mice developed nodal and extranodal lymphomas. Tumor incidence was 50% (70/140) at 18 months of age. The lymphomas demonstrated sheets of large cells with centroblastic morphology, consistent with diffuse large B-cell lymphoma. The mitotic index was high, with the presence of frequent atypical mitotic figures and apoptotic debris laden macrophages, giving a starry sky pattern. C.iMyc/IL-6 mice developed nodal and extra nodal plasma cell tumors (PCT). Tumor incidence was 100% (20/20) at 4–5 months of age. PCT demonstrated sheets of monotonous and atypical plasma cells with prominent nucleoli. In lymphoid tissue containing germinal centers, the sheets of plasma cells were located in the interfollicular areas. There was no bone marrow involvement.

Conclusions: Our findings demonstrate that

1. B6.iMyc mice with CMYC deregulation develop high grade B-cell lymphomas similar to human DLBCL.

2. The activity of deregulated IL-6 appears to enhance and accelerate the oncogenic potential of deregulated CMYC, in the pathogenesis of lymphoid malignancy.

3. IL-6 and/or tumor susceptibility alleles of strain BALB/c cause a remarkable shift in the phenotype of MYC-driven lymphomas from DLBCL to PCT.