B lymphocytes in humans express ZAP‐70 when activated <i>in vivo</i>

Cutrona, Giovanna; Colombo, Monica; Matis, Serena; Reverberi, Daniele; Dono, Mariella; Tarantino, V.; Chiorazzi, Nicholas; Ferrarini, Manlio

doi:10.1002/eji.200526355

Cited by 59 publications

(40 citation statements)

References 35 publications

(60 reference statements)

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“…Tonsil B cells weakly expressed Ror1, which is in accordance with that tonsil B cells are activated cells, showing similarities at the gene level to activated blood B and T cells using a strong (nonphysiological) signal. 17,18 Earlier reports have shown gene expression of ROR1 in neuroectodermal human cell lines as well as in acute leukemia and lymphoma derived cell lines. 10 Our results are supported by recent preliminary reports, also showing expression of Ror1 in CLL.…”

Section: Discussionmentioning

confidence: 99%

Ror1, a cell surface receptor tyrosine kinase is expressed in chronic lymphocytic leukemia and may serve as a putative target for therapy

Daneshmanesh

Mikaelsson

Jeddi‐Tehrani

et al. 2008

Intl Journal of Cancer

156

161

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Gene profiling studies of patients with chronic lymphocytic leukemia (CLL) has revealed increased expression of Ror1, a cell surface receptor tyrosine kinase. The aim of present study was to analyze gene and protein expression of Ror1 in CLL cells and normal blood leukocytes. Gene expression analysis reverse transcriptionpolymerase chain reaction of ROR1 revealed that all patients with CLL (n 5 100) spontaneously expressed ROR1 mRNA whereas enriched blood B and T cells as well as granulocytes from healthy donors (n 5 10) were negative. A strong nonphysiological activation signal (PMA/ionomycin) was required to induce expression in vitro in normal lymphocytes. Major genomic aberrations (mutations or truncation) of ROR1 were not observed. Protein expression was analyzed by Western blot using a panel of polyclonal anti-Ror antibodies as well as flow cytometry. Blood lymphocytes from 18/18 CLL patients, but none of the 10 healthy donors, expressed surface Ror1. The majority of CLL cells exhibited Ror1 surface expression (71% mean; range 36-92%) with a mean fluorescence intensity (MFI) of 20 (range 10-45). The corresponding MFI of CD19 on CLL cells was 26 (range 9-48). There was no difference in the Ror1 protein expression comparing IgVH mutated and unmutated cases as well as progressive and nonprogressive CLL patients. Two different variants of the Ror1 protein, 105 and 130 kDa, were identified. The Ror1 protein expression in patients with CLL but not in normal leukocytes merits further studies of its role in the pathobiology of CLL, which may provide a basis for development of Ror1 directed targeted therapy. ' 2008 Wiley-Liss, Inc. Key words: B-CLL; tyrosine kinase receptors; Ror1Chronic lymphocytic leukemia (CLL) originates from B lymphocytes, which differ in activation and maturation stage and are derived from antigen experienced B cells with different immunoglobulin heavy chain variable (IgVH) gene mutations. 1 Patients with mutated IgVH genes have a better prognosis compared to patients with unmutated genes. 2,3 Global gene expression profiling studies have revealed partly distinguishing but in general overlapping expression profiles in mutated and unmutated leukemic B cells, suggesting a common phenotype. 4,5 Gene expression profiling studies showed a 43.8-fold increase of the orphan receptor tyrosine kinase (RTK) ROR1 in CLL cells. 4 Ror1 is a member of the RTK family of orphan receptors related to muscle specific kinase and Trk neurotrophin receptors. [6][7][8] Ror receptors are cell surface receptors participating in signal transduction, cell-cell interaction, regulation of cell proliferation, differentiation, cell metabolism and survival. 7,9 They are evolutionarily highly conserved between different species e.g., human, mouse, Drosophila and C. elegans, suggesting important biological functions.The human ROR1 gene has a coding region of 2814 bp with a predicted 937 amino acids sequence and 105 kDa protein size including an Ig-like domain, cysteine-rich domain, kringle domain, tyrosine kinase domain and p...

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Section: Discussionmentioning

confidence: 99%

Ror1, a cell surface receptor tyrosine kinase is expressed in chronic lymphocytic leukemia and may serve as a putative target for therapy

Daneshmanesh

Mikaelsson

Jeddi‐Tehrani

et al. 2008

Intl Journal of Cancer

156

161

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“…However, it has recently been shown to be present at early stages of B cell development (12). In addition, other reports show its expression in mature B cells (13) after activation or in subpopulations from tonsil and spleen (12,14).…”

Section: Detection Of Zap-70 Expression At the Proteinmentioning

confidence: 99%

Evaluation of ZAP‐70 expression by flow cytometry in chronic lymphocytic leukemia: A multicentric international harmonization process

Letestu¹,

Rawstron²,

Villamor³

et al. 2006

Cytometry Part B Clinical

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The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous with some patients requiring early therapy whereas others will not be treated for years. The evaluation of an individual CLL patient's prognosis remains a problematic issue. The presence or absence of somatic mutations in the IgVH genes is currently the gold-standard prognostic factor, but this technique is labor intensive and costly. Genomic studies uncovered that 70 kDa zeta-associated protein (ZAP-70) expression was associated with unmutated IgVH genes and ZAP-70 protein expression was proposed as a surrogate for somatic mutational status. Among the available techniques for ZAP-70 detection, flow cytometry is most preferable as it allows the simultaneous quantification of ZAP-70 protein expression levels in CLL cells

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“…The possibility of a biologic difference in CLL cells in the bone marrow when compared with those in the peripheral blood may exist. One study recently identified ZAP-70 positivity in activated non-neoplastic B-cells (4). Perhaps activational status may differentiate CLL cells in the two compartments.…”

Section: Resultsmentioning

confidence: 99%

Comparison of bone marrow and peripheral blood ZAP‐70 status examined by flow cytometric immunophenotyping in patients with chronic lymphocytic leukemia

Sheridan

Mounajjed

Ehrmann

et al. 2006

Cytometry Part B Clinical

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B lymphocytes in humans express ZAP‐70 when activated in vivo

Cited by 59 publications

References 35 publications

Ror1, a cell surface receptor tyrosine kinase is expressed in chronic lymphocytic leukemia and may serve as a putative target for therapy

Ror1, a cell surface receptor tyrosine kinase is expressed in chronic lymphocytic leukemia and may serve as a putative target for therapy

Evaluation of ZAP‐70 expression by flow cytometry in chronic lymphocytic leukemia: A multicentric international harmonization process

Comparison of bone marrow and peripheral blood ZAP‐70 status examined by flow cytometric immunophenotyping in patients with chronic lymphocytic leukemia

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