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Blood, 15 June 2004, Vol. 103, No. 12, pp. 4389-4395. Prepublished online as a Blood First Edition Paper on February 12, 2004; DOI 10.1182/blood-2003-12-4312. This Article Full Text (PDF) All Versions of this Article: 2003-12-4312v1 103/12/4389    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Stevenson, F. K Articles by Caligaris-Cappio, F. Search for Related Content PubMed PubMed Citation Articles by Stevenson, F. K Articles by Caligaris-Cappio, F. Social Bookmarking                   What's this? Submitted December 19, 2003 Accepted January 26, 2004 Chronic lymphocytic leukemia:revelations from the B-cell receptor Freda K Stevenson* and Federico Caligaris-Cappio Cancer Sciences Division, University of Southampton, Southampton, Hampshire, United Kingdom Internal Medicine, Universita Vita Salute San Raffaele and Istituto Scientifico San Raffaele, Milano, Italy * Corresponding author; email: fs{at}soton.ac.uk. The finding that chronic lymphocytic leukemia (CLL) consists of two clinical subsets, distinguished by the incidence of somatic mutations in the Ig V-genes, has clearly linked prognosis to biology. Antigen encounter by the cell of origin is indicated in both subsets by selective but distinct expression of V-genes, with evidence for continuing stimulation post-transformation. The key to distinctive tumor behavior likely relates to the differential ability of the BCR to respond. Both subsets may be undergoing low level signaling in vivo, although analysis of blood cells limits knowledge of critical events in the tissue microenvironment. Analysis of signal competence in vitro reveals that generally unmutated CLL continues to respond, whereas mutated CLL is anergized. Differential responsiveness may reflect the increased ability of post-germinal center B cells to be triggered by antigen, leading to long-term anergy. This could minimize cell division in mutated CLL and account for prognostic differences. Unifying features of CLL include low responsiveness, expression of CD25 and production of immunosuppressive cytokines. These properties are reminiscent of regulatory T cells, and suggest that the cell of origin of CLL might be a regulatory B cell. Continuing regulatory activity, mediated via autoantigen, could suppress Ig production and lead to disease-associated hypogammaglobulinemia. 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