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).

[1]  Arthur Weiss,et al.  ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. , 2004, The New England journal of medicine.

[2]  T. Kipps,et al.  CpG oligodeoxynucleotides enhance the capacity of adenovirus-mediated CD154 gene transfer to generate effective B-cell lymphoma vaccines. , 2003, Cancer research.

[3]  Adrian Wiestner,et al.  ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. , 2003, Blood.

[4]  Emili Montserrat,et al.  ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. , 2003, The New England journal of medicine.

[5]  D. Oscier,et al.  Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia. , 2003, Blood.

[6]  Arthur Weiss,et al.  Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. , 2002, Blood.

[7]  T. Kurosaki,et al.  BLNK: molecular scaffolding through ‘cis’‐mediated organization of signaling proteins , 2002, The EMBO journal.

[8]  D. Oscier,et al.  The alternative transcript of CD79b is overexpressed in B-CLL and inhibits signaling for apoptosis. , 2002, Blood.

[9]  R. Aebersold,et al.  The Direct Recruitment of BLNK to Immunoglobulin α Couples the B-Cell Antigen Receptor to Distal Signaling Pathways , 2002, Molecular and Cellular Biology.

[10]  David Botstein,et al.  Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia , 2001, The Journal of experimental medicine.

[11]  E. Cesarman,et al.  Survival of leukemic B cells promoted by engagement of the antigen receptor. , 2001, Blood.

[12]  J. Benichou,et al.  Expression of unmutated VH genes is a detrimental prognostic factor in chronic lymphocytic leukemia. , 2000, Blood.

[13]  I. Johnson,et al.  Chemical and physiological characterization of fluo-4 Ca(2+)-indicator dyes. , 2000, Cell calcium.

[14]  T. Kurosaki,et al.  BLNK: connecting Syk and Btk to calcium signals. , 2000, Immunity.

[15]  T J Hamblin,et al.  Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. , 1999, Blood.

[16]  Andrew C. Chan,et al.  BLNK Required for Coupling Syk to PLCγ2 and Rac1-JNK in B Cells , 1999 .

[17]  T. Kurosaki,et al.  BLNK required for coupling Syk to PLC gamma 2 and Rac1-JNK in B cells. , 1999, Immunity.

[18]  L. Rassenti,et al.  Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. , 1998, The Journal of clinical investigation.

[19]  C. Turck,et al.  BLNK: a central linker protein in B cell activation. , 1998, Immunity.

[20]  T. Kipps.  Signal transduction pathways and mechanisms of apoptosis in CLL B-lymphocytes: their role in CLL pathogenesis. , 1997, Hematology and cell therapy.

[21]  V. Lang,et al.  Normal Syk protein level but abnormal tyrosine phosphorylation in B-CLL cells , 1997, Leukemia.

[22]  J. Brugge,et al.  Protein tyrosine kinases Syk and ZAP-70 display distinct requirements for Src family kinases in immune response receptor signal transduction. , 1997, Journal of immunology.

[23]  A. Veillette,et al.  Differential Intrinsic Enzymatic Activity of Syk and Zap-70 Protein-tyrosine Kinases* , 1996, The Journal of Biological Chemistry.

[24]  T. Kurosaki,et al.  Reconstitution of Syk function by the ZAP-70 protein tyrosine kinase. , 1995, Immunity.

[25]  R. V. van Lier,et al.  Antigen receptor nonresponsiveness in chronic lymphocytic leukemia B cells. , 1995, Blood.

[26]  C. Disteche,et al.  Molecular cloning of human Syk. A B cell protein-tyrosine kinase associated with the surface immunoglobulin M-B cell receptor complex. , 1994, The Journal of biological chemistry.

[27]  K. Rauen,et al.  Identification of a gene encoding a novel protein-tyrosine kinase containing SH2 domains and ankyrin-like repeats. , 1994, Oncogene.

[28]  P. Debré,et al.  Defective calcium response in B-chronic lymphocytic leukemia cells. Alteration of early protein tyrosine phosphorylation and of the mechanism responsible for cell calcium influx. , 1993, Journal of immunology.

[29]  C. Hivroz,et al.  Cross‐linking of membrane IgM on B CLL cells: dissociation between intracellular free Ca2+ mobilization and cell proliferation , 1988, European journal of immunology.

[30]  P. Debré,et al.  Functional heterogeneity of B-CLL lymphocytes: dissociated responsiveness to growth factors and distinct requirements for a first activation signal. , 1987, Blood.

[31]  C. Hivroz,et al.  Heterogeneity of responsiveness of chronic lymphocytic leukemic B cells to B cell growth factor or interleukin 2 , 1986, European journal of immunology.