Spontaneous Development of Plasmacytoid Tumors in Mice with Defective Fas–Fas Ligand Interactions

Abstract

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− 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.

Inducible resistance to Fas-mediated apoptosis in B cells

“…Inasmuch as inhibition of Fas signaling for cell death is associated with tumor development and progression, it appears that Fas-mediated apoptosis constitutes at least a portion of anti-tumor immunity, and that some malignancies take advantage of mechanisms that block Fas killing to maintain viability and co-exist within the framework of a normal immune system [100,101], [150][151][152][153]. The mechanisms utilized by malignant cells may represent perversions of the physiological means by which B cells normally inhibit susceptibility to Fas-mediated apoptosis in a receptor-specific fashion.…”

Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome

“…In this murine model, B-cell expansion is attributed to CD5 Ϫ /CD23 low B cells and not CD5 ϩ B cells. 24,25 Furthermore, it has been shown that CD5 Ϫ B cells are responsible for the production of autoantibodies in lpr mice. 26 CD5 ϩ B cells are involved in another murine model of lupus erythematosus, the New Zealand black-(NZB) and New Zealand white (NZW)-derived strain.…”

Transgenic models of lymphoid neoplasia and development of a pan-hematopoietic vector

“…Older lpr mice, particularly those lacking T cells, develop plasmacytoma (Peng et al, 1996;Davidson et al, 1998). Moreover, the lpr mutation accelerates lymphoma onset in Em-Lmyc transgenic mice (ZoÈ rnig et al, 1995) and, as mentioned above, cooperates with bcl-2 in leukemogenesis (Traver et al, 1998).…”