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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4424-4431.
Prepublished online as a Blood First Edition Paper on January 25, 2007; DOI 10.1182/blood-2006-11-056648.
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Submitted November 8, 2006
Accepted January 17, 2007
Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status
C Ian Mockridge, Kathleen N Potter, Isla Wheatley, Louise A Neville, Graham Packham, and Freda K. Stevenson*
Molecular Immunology Group, Tenovus Laboratory, Cancer Research UK Clinical Centre, Cancer Sciences Division, University of Southampton, Southampton, United Kingdom
* Corresponding author; email: fs{at}soton.ac.uk.
The two subsets of CLL, of worse or better prognosis, likely derive from pre-GC unmutated B cells, or post-GC mutated B cells respectively. Different clinical behavior could relate to the ability of tumor cells to respond to sIg-mediated signals. Unmutated cases (U-CLL) have an increased ability to phosphorylate p72Syk in response to sIgM ligation, compared to mutated (M-CLL). We now confirm and further investigate this differential signalling in a large cohort by [Ca2+]i mobilization. Cases responding to sIgM ligation express higher levels of CD38, ZAP-70 and sIgM. However, CD38 does not influence signalling in vitro or associate with response in bimodal CD38-expressing cases. Similarly, ZAP-70 expression is not required for response in either U-CLL or M-CLL. Strikingly, partially or completely anergized sIgM responses from each subset can recover both sIgM expression and signal capacity spontaneously in vitro or following capping/endocytosis. This provides direct evidence for engagement of putative antigen in vivo. Signaling via sIgD differs markedly being almost universally positive in both U-CLL and M-CLL, with no association with CD38 or ZAP-70 expression. Downstream signalling pathways therefore appear intact in CLL, locating anergy to sIgM, mainly in M-CLL. Integration of differential isotype-specific effects mediated by (auto)antigen may determine tumor behavior.
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