Heterogeneity of responsiveness of chronic lymphocytic leukemic B cells to B cell growth factor or interleukin 2

Hivroz, Claire; Grillot‐Courvalin, Catherine; Brouet, Jean‐Claude; Séligmann, M

doi:10.1002/eji.1830160821

Cited by 61 publications

(18 citation statements)

References 12 publications

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“…The constitutive expression of functional HMW-BCGF R on CLL cells (1) suggests that HMW-BCGF may be involved in the clonal expansion of malignantly transformed B lymphocytes and (2) recommends future long-term studies of its role in leukemogenesis and disease progression in CLL. Our observation that not all CLLs expressed functional HMW-BCGF R provides suggestive evidence that CLL may be a biologically heterogeneous group of diseases, which supports and extends the findings of Karray et al (27), and Hivroz et al (28). Whether or not biologically and prognostically distinct subgroups of patients can be identified based on HMW-BCGF R expression will be the subject of separate long-term studies.…”

Section: Discussionsupporting

confidence: 89%

Detection and characterization of human high molecular weight B cell growth factor receptors on leukemic B cells in chronic lymphocytic leukemia.

Uckun¹,

Fauci²,

Chandan-Langlie³

et al. 1989

J. Clin. Invest.

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Section: Discussionsupporting

confidence: 89%

Detection and characterization of human high molecular weight B cell growth factor receptors on leukemic B cells in chronic lymphocytic leukemia.

Uckun¹,

Fauci²,

Chandan-Langlie³

et al. 1989

J. Clin. Invest.

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“…[20][21][22] Semiquantitative studies found that CLL cells with unmutated Ig genes had greater increases in the levels of tyrosine-phosphorylated proteins following IgM crosslinking than did CLL cells that expressed mutated Ig receptors. 6,23 Although we noted that increased IgM signaling capacity also was associated with expression of ZAP-70, 6 this could have been secondary to factors other than ZAP-70 that might also have been associated with leukemia cells that express unmutated Ig genes.…”

Section: Discussionmentioning

confidence: 99%

ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia

Chen

Apgar

Huynh

et al. 2005

Blood

219

174

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IntroductionThe B cells of patients with chronic lymphocytic leukemia (CLL) can be segregated into one of at least 2 major subsets based upon the mutational status of the expressed immunoglobulin (Ig) heavychain variable region genes (IgV H ). 1 Patients with CLL cells that express unmutated IgV H tend to have a relatively aggressive clinical course when compared with patients who have CLL cells that express IgV H with somatic mutations. 2,3 Although these 2 types share a common gene expression profile, isolated CLL B cells of these 2 subgroups can be distinguished from each other by the differential expression of a relatively small subset of genes. 4 One of these genes encodes the zeta-associated protein of 70 kDa (ZAP-70), a receptor-associated protein tyrosine kinase (PTK) expressed by T lymphocytes and natural killer cells (NK cells) but not by normal B cells or most cases of CLL with mutated IgV H .The functional significance of ZAP-70 gene expression in this subset of CLL B cells is unknown. Irrespective of the expression of ZAP-70, CLL cells generally express similar levels of p72 Syk , a related PTK. 5,6 B cells use p72 Syk for signal transduction via the B-cell receptor (BCR) complex. 7 Following BCR ligation, p72 Syk is recruited to the phosphorylated immunoreceptor tyrosine-based activation motifs (ITAM) of the activated BCR complex, where it subsequently becomes phosphorylated and activated. 8 In normal B cells, activated p72 Syk phosphorylates several proteins, including BLNK (for B-cell linker protein, also known as SLP-65, BASH, or BCA). 9-11 BLNK serves as a docking site for a number of signaling molecules, including Btk, Vav, and phospholipase C-gamma (PLC␥). Phosphorylation and activation of PLC␥ lead to hydrolysis of the polyphosphoinositides and subsequent production of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), which serve to increase intracellular calcium (Ca 2ϩ ) and activate protein kinase C (PKC) and Ras, respectively.Recent studies indicate that CLL cells that express ZAP-70 mRNA have levels of ZAP-70 protein that are similar to those of normal blood T cells. 6,12,13 Furthermore, treatment of ZAP-70 ϩ CLL cells with anti-induced significantly greater tyrosine phosphorylation of cytosolic proteins, including p72 Syk , than CLL cells that lacked ZAP-70. 6 Moreover, following treatment with anti-, ZAP-70 underwent tyrosine phosphorylation and became associated with surface and CD79b, arguing that this PTK might enhance BCR receptor signaling in CLL B cells. However, the contributions of ZAP-70 to the activation of downstream adaptor proteins, such as BLNK or PLC␥, or to changes in intracellular Ca 2ϩ in response to Ig receptor signaling in CLL have not been resolved.Resolution of the role that ZAP-70 plays in Ig receptor signaling in CLL is important, as this protein tyrosine kinase is not an obvious candidate to enhance BCR signaling, given that CLL cells generally also express p72 Syk . 6 Indeed, p72 Syk has an approximately 100-fold greater intrinsic PTK activity than...

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“…(35). Moreover, normal B cells (36) and T cells (37) isolated from these patients also have markedly diminished responsiveness. Here, by contrast, we demonstrate a mitogen for CLL cells that has no effect on normal cells.…”

mentioning

confidence: 99%

Prolactin-immunoglobulin G complexes from human serum act as costimulatory ligands causing proliferation of malignant B lymphocytes.

Walker

Montgomery

Saraiya

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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Several lines of evidence indicate that immunoglobulin-bound prolactin found in human serum is not a conventional complex between an anti-prolactin antibody and prolactin but a different type of association of prolactin with the Fab portion of IgG heavy chains. The complex of prolactin with IgG was purified from serum by anti-human prolactin affinity chromatography and was shown to contain close to 1 mole of N8-(ryglutamyl)lysine crosslinks per mole of complex, a characteristic feature in structures crosslinked by transglutaminase. Interestingly, the complex caused a proliferation of cells from a subset of patients with chronic lymphocytic leukemia, while it was inactive in a cell proliferation prolactin bioassay. By contrast, human prolactin stimulated the proliferation of cells in the bioassay but had no effect on the complex-responsive cells from the patients. Competition studies with prolactin and free Fc fragment of IgG demonstrated a necessity for engaging both the prolactin and the immunoglobulin receptors for proliferation. More importantly, competition for the growth response by free prolactin and IgG suggests both possible reasons for the slow growth of this neoplasm as well as avenues for control of the disease.

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Heterogeneity of responsiveness of chronic lymphocytic leukemic B cells to B cell growth factor or interleukin 2

Cited by 61 publications

References 12 publications

Detection and characterization of human high molecular weight B cell growth factor receptors on leukemic B cells in chronic lymphocytic leukemia.

Detection and characterization of human high molecular weight B cell growth factor receptors on leukemic B cells in chronic lymphocytic leukemia.

ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia

Prolactin-immunoglobulin G complexes from human serum act as costimulatory ligands causing proliferation of malignant B lymphocytes.

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