Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by V-H-gene mutational status
Mockridge, C. Ian, Potter, Kathleen N., Wheatley, Isla, Neville, Louise A., Packham, Graham and Stevenson, Freda K. (2007) Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by V-H-gene mutational status. Blood, 109, (10), 4424-4431. (doi:10.1182/blood-2006-11-056648).
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The 2 subsets of chronic lymphocytic leukemia (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 surface (slg)-mediated signals. Unmutated cases (U-CLL) have an increased ability to phosphorylate p72(Syk) in response to slgM ligation compared to mutated cases (M-CLL). We now confirm and further investigate this differential signaling in a large cohort by [Ca2+], mobilization. Cases responding to slgM ligation express higher levels of CD38, ZAP-70, and slgM. However, CD38 does not influence signaling 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 slgM responses from each subset can recover both slgM expression and signal capacity spontaneously in vitro or following capping/enclocytosis. This provides direct evidence for engagement of putative antigen in vivo. Signaling via slgD differs markedly being almost universally positive in both U-CLL and M-CLL, with no association with CD38 or ZAP-70 expression. Downstream signaling pathways, therefore, appear intact in CLL, locating anergy to slgM, mainly in M-CLL. Integration of differential isotype-specific effects mediated by (auto)antigen may determine tumor behavior.
|Keywords:||pathway, immunoglobulin, b cell, tyrosine kinase, tumor-cells, cell, surface, zap-70 expression, pathways, cohort, chronic lymphocytic-leukemia, activation, time, responses, expression, b-cell-receptor, prognosis, leukemia, antigen, in-vitro, lymphocytic-leukemia, cross-linking, antigen receptor, cd38 expression, tumor, cll, cd38, cells, b-cells, vivo, in-vivo, zap-70, surface igm|
|Subjects:||R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Q Science > QH Natural history > QH426 Genetics
|Divisions:||University Structure - Pre August 2011 > School of Medicine > Cancer Sciences
|Date Deposited:||12 Nov 2008|
|Last Modified:||23 Jul 2012 12:02|
|Contributors:||Mockridge, C. Ian (Author)
Potter, Kathleen N. (Author)
Wheatley, Isla (Author)
Neville, Louise A. (Author)
Packham, Graham (Author)
Stevenson, Freda K. (Author)
|Date:||15 May 2007|
|RDF:||RDF+N-Triples, RDF+N3, RDF+XML, Browse.|
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