Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia.
The mutational status of tumor immunoglobulin V(H) genes is providing a powerful prognostic marker for chronic lymphocytic leukemia (CLL), with patients having tumors expressing unmutated V(H) genes being in a less favorable subset. However, the biologic differences correlating with V(H) gene status that could determine the clinical course of the disease are unknown. Here we show that differing responses to IgM ligation are closely associated with V(H) gene status. Specifically, 80% of cases with unmutated V(H) genes showed increased global tyrosine phosphorylation following IgM ligation, whereas only 20% of samples with mutated V(H) genes responded (P =.0002). There was also an association between response to IgM ligation and expression of CD38 (P =.015). The Syk kinase, critical for transducing B-cell receptor (BCR)- derived signals, was constitutively present in all CLL samples, and there was a perfect association between global phosphorylation and induction of phosphorylation/activation of Syk. Nonresponsiveness to anti-IgM could be circumvented by ligation of IgD (10 of 15 samples tested) or the BCR-associated molecule CD79alpha (12 of 15 samples tested). These results suggest that multiple mechanisms underlie nonresponsiveness to anti-IgM in CLL and that retained responsiveness to anti-IgM contributes to the poor prognosis associated with the unmutated subset of CLL. The prognostic power of the in vitro response to IgM ligation remains to be determined in a large series, but the simple technology involved may present an alternative or additional test for predicting clinical course.
Lanham
Stuart
S
Molecular Immunology Group, Tenovus Research Laboratory, Southampton University Hospitals Trust, Southampton, United Kingdom.
Hamblin
Terry
T
Oscier
David
D
Ibbotson
Rachel
R
Stevenson
Freda
F
Packham
Graham
G
D036541:ADP-ribosyl Cyclase / Q000378:metabolism*; D051997:ADP-ribosyl Cyclase 1; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D004792:Enzyme Precursors / Q000032:analysis / Q000378:metabolism; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D016130:Immunophenotyping; D047908:Intracellular Signaling Peptides and Proteins; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D000072377:Syk Kinase
D000906:Antibodies; D015703:Antigens, CD; D004792:Enzyme Precursors; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1