A cultured malignant B-1 line serves as a model for Richter's syndrome.

Abstract

Human chronic lymphocytic leukemia (CLL) is a malignancy of B-1 cells characterized by the accumulation of mature appearing, long lived, slow growing B-1 cells in peripheral blood. CLL occasionally evolves into an aggressive large cell lymphoma termed Richter's syndrome. NZB mice can be used to model the early stage of CLL because aged NZB mice can spontaneously develop slow growing malignant B-1 cell clones. The malignant NZB B-1 clones fail to grow in culture and are typically carried in vivo as passaged lines. During serial passage, an aggressive lymphoma developed as a result of a continued transformation of the original B-1 clone, similar to the development of Richter's syndrome. An in vitro cell line was established from the aggressive lymphoma, which was stromal dependent and could rapidly metastasize when passaged into recipient animals. Analysis of adhesion molecules did not reveal any consistent characteristics that could account for the metastatic potential of the Richter's-like cells. In addition, the aggressive in vitro line had the identical heavy chain sequence as the slow growing NZB malignant B-1 clones. The in vitro and in vivo aggressive B-1 cells had very high levels of IL-10 message, and underwent more apoptosis in response to anti-IgM than did nonaggressive B-1 clones. Taking these characteristics together, we have composed a comprehensive animal model system for human CLL that includes both the aged NZB mice for the early stage and the recipients of the in vitro B-1 line for the late stage or Richter's syndrome. This model system can be used to study, not only the ontogeny and genetic linkage of CLL, but also the regulatory factors involved in transformation and growth both in vivo and in vitro.

Mouse models of chronic lymphocytic leukemia and Richter transformation: what we have learnt and what we are missing

“…Raveche and her group within the context of the NZB mouse strain ( Table 3 ). Multiple passages through successive F1 recipients of a clonal line originating from an old NZB mouse resulted in a transformed clone localizing to the LNs and liver with the distinct features of the human RT ( 80 , 88 , 89 ). Unlike the original CLL-like clone, the murine secondary transformation recapitulated the pathology of RT with the disruption of the normal tissue architecture and the massive infiltration of the spleen, LNs, and liver by large cells with cleaved nuclei and evident nucleoli ( 88 ).…”