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Blood, 2 July 2009, Vol. 114, No. 1, pp. 3.
Mighty mouseTHE OHIO STATE UNIVERSITY Abstract In this issue of Blood, ter Brugge and colleagues describe the results of their efforts to express SV40 T antigen in mature B cells of mice.1 As a consequence of T antigen expression, B cells develop normally but, upon aging, mice show an accumulation of monoclonal CD5+ B cells and have a chronic lymphocytic leukemia-like phenotype. Chronic lymphocytic leukemia (CLL) is diagnosed on the basis of a specific malignant B-cell phenotype, co-expressing CD19 and CD5 along with dim surface expression of immunoglobulin. The clonal B cell of CLL has a low proliferation rate but disrupted apoptosis, both due to primary tumor features as well as interactions with stromal elements. Genomic studies demonstrate that CLL cases have a common gene expression profile but can be divided into 2 molecular subsets, based on immunoglobulin heavy chain variable region (IgVH) gene mutational status. Since the publication by Bichi and Croce in 2002 describing the TCL-1 transgenic mouse,2 the CLL world has been reinvigorated by the availability of a suitable animal model for this disease. Further discoveries have continued this progress, including reproduction of CLL T-cell defects3 and their immunotherapeutic reversibility4 in the TCL-1 mouse and microRNA 16 loci abnormalities in the New Zealand Black mice.5 The article by ter Brugge et al in this issue is yet another example of this effort toward the development of an ideal in vivo representation of CLL. ter Brugge et al insert the SV40 large T antigen opposite the orientation of the immunoglobulin heavy (IgH) chain locus along with the IgH intronic enhancer Eµ. The resultant IgH.TEµ mice have normal B-cell development but, at around 6 months, mice exhibit a monoclonal expansion of CD19+/CD5+ B cells that express a single Ig L chain (kappa or lambda) that is detectable by flow cytometry. By 10 months, all mice develop leukemia detectable in peripheral blood, spleen, and bone marrow, and have enlarged spleen and lymph nodes reminiscent of human CLL. Genetically IgH.TEµ mice were found to have germline (unmutated) IgVH sequences, which is considered to be the more aggressive form of CLL. The distinctly positive influence of p53 deletion on the development of leukemia indicates another similarity to the human disease.
Of course, any new model presents new questions. Does the IgH.TEµ SV40 large T-dependent model have T-cell defects, as found in CLL patients and TCL-1 mouse model? Is the leukemia transplantable? What are additional similarities or differences compared with human CLL, such as in spontaneous apoptosis, Bcl-2 family member involvement and abnormalities, chromosomal and epigenetic profiles, and the activity of NF- At presentation, most CLL patients are asymptomatic, but a subset will progress to symptomatic disease. Since treatments available to date have shown no significant improvement in survival, it is only after symptoms appear that therapy is initiated. Unfortunately, this may be too late. Early intervention prior to symptomatic disease may be our best chance to substantially impact overall survival in CLL patients, even using the potent and targeted agents now under evaluation and on the horizon. The uncertainty about how to predict which patients will do well with what therapy remains one of the most pressing issues in CLL. If phenotypic, biologic, and genetic similarities between this novel model and aggressive human CLL can continue to be established, it will indeed present a powerful tool to help us understand not just the biology of this complex disease, but strategies to select the most effective therapies in the long term.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
REFERENCES
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| Copyright © 2009 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
B and other key signaling pathways? How do these animals respond to established CLL therapies? Each of these characteristics can be used to further bolster the relevance and utility of this model in the investigation of human CLL. 