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J. Exp. Med.,
Volume 187, Number 11, June 1, 1998 1825-1838
By
From the * Laboratory of Genetics and the B cell malignancies arise with increased frequency in aging individuals and in patients with genetic or acquired immunodeficiency (e.g., AIDS) or autoimmune diseases. The mechanisms of
lymphomagenesis in these individuals are poorly understood. In this report we investigated the
possibility that mutations at the Fas (lpr) and Fasl (gld) loci, which prevent Fas-mediated apoptosis and cause an early onset benign lymphoid hyperplasia and autoimmunity, also predispose
mice to malignant lymphomas later in life. Up to 6 mo of age, hyperplasia in lpr and gld mice
results from the predominant accumulation of polyclonal T cell subsets and smaller numbers of
polyclonal B cells and plasma cells. Here, we examined C3H-lpr, C3H-gld, and BALB-gld mice
6-15 mo of age for the emergence of clonal T and B cell populations and found that a significant proportion of aging mice exclusively developed B cell malignancies with many of the hallmarks of immunodeficiency-associated B lymphomas. By 1 yr of age, ~60% of BALB-gld and
30% of C3H-gld mice had monoclonal B cell populations that grew and metastasized in scid recipients but in most cases were rejected by immunocompetent mice. The tumors developed in
a milieu greatly enriched for plasma cells, CD23 Registry of Experimental Cancers, National Cancer
Institute, National Institutes of Health, Bethesda, Maryland 20892
B cells and immunodeficient memory T cells
and variably depleted of B220+ DN T cells. Growth factor-independent cell lines were established from five of the tumors. The majority of the tumors were CD23 and IgH isotype
switched and a high proportion was CD5+ and dull Mac-1+. Considering their Ig secretion
and morphology in vivo, most tumors were classified as malignant plasmacytoid lymphomas.
The delayed development of the gld tumors indicated that genetic defects in addition to the
Fas/Fasl mutations were necessary for malignant transformation. Interestingly, none of the tumors showed changes in the genomic organization of c-Myc but many had one or more somatically-acquired MuLV proviral integrations that were transmitted in scid passages and cell lines.
Therefore, insertional mutagenesis may be a mechanism for transformation in gld B cells. Our
panel of in vivo passaged and in vitro adapted gld lymphomas will be a valuable tool for the future identification of genetic abnormalities associated with B cell transformation in aging and
autoimmune mice.
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