Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia.
We examined isolated leukemia B cells of patients with chronic lymphocytic leukemia (CLL) for expression of zeta-associated protein 70 (ZAP-70). CLL B cells that have nonmutated immunoglobulin variable region genes (V genes) expressed levels of ZAP-70 protein that were comparable to those expressed by normal blood T cells. In contrast, CLL B cells that had mutated immunoglobulin variable V genes, or that had low-level expression of CD38, generally did not express detectable amounts of ZAP-70 protein. Leukemia cells from identical twins with CLL were found discordant for expression of ZAP-70, suggesting that B-cell expression of ZAP-70 is not genetically predetermined. Ligation of the B-cell receptor (BCR) complex on CLL cells that expressed ZAP-70 induced significantly greater tyrosine phosphorylation of cytosolic proteins, including p72(Syk), than did similar stimulation of CLL cells that did not express ZAP-70. Also, exceptional cases of CLL cells that expressed mutated immunoglobulin V genes and ZAP-70 also experienced higher levels tyrosine phosphorylation of such cytosolic proteins following BCR ligation. Following BCR ligation, ZAP-70 underwent tyrosine phosphorylation and became associated with surface immunoglobulin and CD79b, arguing for the involvement of ZAP-70 in BCR signaling. These data indicate that expression of ZAP-70 is associated with enhanced signal transduction via the BCR complex, which may contribute to the more aggressive clinical course associated with CLL cells that express nonmutated immunoglobulin receptors.
Chen
Liguang
L
Division of Hematology/Oncology, Department of Medicine, University of California, San Diego for the CLL Research Consortium, San Diego, CA, USA.
Widhopf
George
G
Huynh
Lang
L
Rassenti
Laura
L
Rai
Kanti R
KR
Weiss
Arthur
A
Kipps
Thomas J
TJ
D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004200:Diseases in Twins; D004792:Enzyme Precursors / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D015322:Gene Rearrangement, B-Lymphocyte; D005803:Genes, Immunoglobulin; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D015398:Signal Transduction; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase
D004792:Enzyme Precursors; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human