ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia.
Chronic lymphocytic leukemia (CLL) B cells that express unmutated immunoglobulin heavy-chain variable region genes (IgV(H)) generally express ZAP-70, in contrast to normal B cells or most CLL cases with mutated IgV(H). Following IgM ligation, ZAP-70+ CLL cells had significantly higher levels of phosphorylated p72(Syk), BLNK, and phospholipase-Cgamma (PLCgamma) and had greater[Ca2+]i flux than did ZAP-70-negative CLL cases, including unusual ZAP-70-negative cases with unmutated IgV(H). IgM ligation of ZAP-70-negative CLL B cells infected with an adenovirus vector encoding ZAP-70 induced significantly greater levels of phosphorylated p72(Syk), BLNK, and PLCgamma and had greater[Ca2+]i flux than did similarly stimulated, noninfected CLL cells or CLL cells infected with a control adenovirus vector. We conclude that expression of ZAP-70 in CLL allows for more effective IgM signaling in CLL B cells, a feature that could contribute to the relatively aggressive clinical behavior generally associated with CLL cells that express unmutated IgV(H).
Chen
Liguang
L
Division of Hematology/Oncology, Department of Medicine, University of California, San Diego, 9500 Gilman Dr, UCSD School of Medicine, La Jolla, CA 92093, USA.
Apgar
John
J
Huynh
Lang
L
Dicker
Frank
F
Giago-McGahan
Teresa
T
Rassenti
Laura
L
Weiss
Arthur
A
Kipps
Thomas J
TJ
D048868:Adaptor Proteins, Signal Transducing; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M / Q000502:physiology*; D007135:Immunoglobulin Variable Region; D047908:Intracellular Signaling Peptides and Proteins; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D000072377:Syk Kinase; D010738:Type C Phospholipases / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D002352:Carrier Proteins; D004792:Enzyme Precursors; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D010738:Type C Phospholipases; D051966:Phospholipase C gamma