Proliferation characteristics in pediatric Hodgkin's lymphoma point to a cell cycle arrest in the G1 phase

Tiemann, Markus; Claviez, Alexander; Lüders, H; Zimmermann, Martin; Schellong, G; Dörffel, W; Parwaresch, Reza

doi:10.1038/modpathol.3800466

Cited by 15 publications

(6 citation statements)

References 34 publications

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“…In human testis, spermatogonia and spermatocytes express CT45 antigen and harbor the Ki-67 antigen, a protein only expressed in proliferating cells from G 1 until the end of mitosis (31). Immunostainings of Hodgkin's lymphoma with a mAb specific to the Ki-67 antigen showed that f80% of the Hodgkin and Reed-Sternberg cells were at least in G 1 cell cycle phase, showing that CT45 antigen expression is probably associated with cell proliferation in these cells (32). Nuclear expression of CT45 in a small fraction of resting cells of the Hodgkin's cell line L428 could be a consequence of the process of cell culturing.…”

Section: Discussionmentioning

confidence: 99%

Characterization and Expression of CT45 in Hodgkin's Lymphoma

Heidebrecht¹,

Claviez²,

Kruse³

et al. 2006

Clinical Cancer Research

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Purpose: The monoclonal antibody Ki-A10 (IgG1) generated after immunization of mice with Hodgkin's lymphoma cell line L428 detects a nuclear antigen in human tissues with a restricted distribution pattern similar to cancer/testis antigens.The aim of this study was to characterize the antigen and to determine the expression profile in Hodgkin's lymphoma. Experimental Design: The half-life and phosphorylation of the antigen were determined by radiolabeling. The antigen was characterized by immunopurification and sequencing. Demethylation of genes is used to induce cancer/testis antigens. Ki-A10-negative cells were treated with 5-aza-2 ¶-deoxycytidine. The Ki-A10 expression in paraffin-embedded tumors was determined immunohistochemically. Results: Immunopurification of the 25/22-kDa antigen and sequencing revealed a peptide of 14 amino acids corresponding to the gene product of the newly described gene family MGC27005, located on chromosome Xq26.3, now termed CT45. CT45 is significantly phosphorylated and down-regulated during mitosis. Demethylation of CT45-negative HeLa cells and stimulated peripheral blood lymphocytes induced CT45 expression. Except testis, immunohistochemical stainings of normal tissues, reactive lymphoid lesions, and most malignant tumors were negative. In comparison, 54 of 99 (55%) samples from pediatric and adolescent Hodgkin's lymphoma patients enrolled in the multicenter trial HD-95 stained Ki-A10 positive. Ki-A10 expression correlated with histologic subtypes (nodular sclerosis Hodgkin's lymphoma 68% versus mixed cellularity Hodgkin's lymphoma 40% versus nodular lymphocyte predominant Hodgkin's lymphoma 9%; P < 0.001).Conclusions: Ki-A10 is the first monoclonal antibody that detects CT45. As benign lymphoid lesions did not express CT45, the use of Ki-A10 antibody will facilitate the discrimination of Hodgkin's lymphoma from reactive lymphadenopathies.

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Section: Discussionmentioning

confidence: 99%

Characterization and Expression of CT45 in Hodgkin's Lymphoma

Heidebrecht¹,

Claviez²,

Kruse³

et al. 2006

Clinical Cancer Research

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“…However, an immunohistochemical study of 224 pediatric patients enrolled in the German Society for Pediatric Oncology and Hematology (GPOH) HD-90 and HD-95 trials found that high Ki-67 expression in HRS cells as well as lymphocytic and histiocytic cells was not related to either advanced clinical stage or poor clinical outcome. Meanwhile, expression of the cell cycle marker repp86, which generally becomes detectable at the G1-S boundary, was low, implying that HRS or lymphocytic and histiocytic cells are arrested in the G1 phase of the cell cycle [41]. Better outcomes in pediatric HL cases that have a high proliferative index are attributed to increased susceptibility of proliferative cells to chemotherapeutic drugs [17, 42, 43].…”

Section: Molecular and Genetic Prognostic Biomarkersmentioning

confidence: 99%

Pediatric Hodgkin lymphoma- biomarkers, drugs, and clinical trials for translational science and medicine

et al. 2016

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Hodgkin lymphoma (HL) is a lymphoid malignancy that is typically derived from germinal-center B cells. EBV infection, mutations in NF-κB pathway genes, and genetic susceptibility are known risk factors for developing HL. CD30 and NF-κB have been identified as potential biomarkers in pediatric HL patients, and these molecules may represent therapeutic targets. Although current risk adapted and response based treatment approaches yield overall survival rates of >95%, treatment of relapse or refractory patients remains challenging. Targeted HL therapy with the antibody-drug conjugate Brentuximab vedotin (Bv) has proven to be superior to conventional salvage chemotherapy and clinical trials are being conducted to incorporate Bv into frontline therapy that substitutes Bv for alkylating agents to minimize secondary malignancies. The appearance of secondary malignancies has been a concern in pediatric HL, as these patients are at highest risk among all childhood cancer survivors. The risk of developing secondary leukemia following childhood HL treatment is 10.4 to 174.8 times greater than the risk in the general pediatric population and the prognosis is significantly poorer than the other hematological malignancies with a mortality rate of nearly 100%. Therefore, identifying clinically valuable biomarkers is of utmost importance to stratify and select patients who may or may not need intensive regimens to maintain optimal balance between maximal survival rates and averting late effects. Here we discuss epidemiology, risk factors, staging, molecular and genetic prognostic biomarkers, treatment for low and high-risk patients, and the late occurrence of secondary malignancies in pediatric HL.

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“…Although we did not examine the proliferation rates of HRS cells in this series, previous studies have reported prognostic relevance of proliferation rates of HRS cells in cHL. [47][48][49] It is conceivable that the superior survival of cHL with MET and/or MST1R expression in the present study may also involve higher proliferation rate of HRS cells. In our study, MET or MST1R protein correlated with each level of mRNA.…”

Section: Discussionmentioning

confidence: 76%

MET and MST1R as prognostic factors for classical Hodgkin's lymphoma

et al. 2013

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MST1R (RON) and MET are receptor tyrosine kinase gene family members that form a noncovalent complex on the cell surface, a critical step in tumor progression. A recent study suggested a prognostic role of MET expression in Hodgkin/Reed-Sternberg (HRS) cells in classical Hodgkin's lymphoma (cHL). The purpose of this study was to examine the prognostic significance of MET and MST1R expression in cHL. The prognostic impact of MET and MST1R was examined in 100 patients with cHL (median age: 32 years) by immunohistochemistry and mRNA in situ hybridization. The median follow-up time was 95 months (interquartile range: 42-126 months). MET or MST1R protein expression was associated with high MET or MST1R mRNA expression, respectively. Thirty-eight patients (38%) expressed MET protein in HRS cell, which was associated with better overall survival (P ¼ 0.004). Twenty-six patients (26%) expressed MST1R protein, which was associated with better overall survival (P ¼ 0.022) and event-free survival (P ¼ 0.021). Multivariate analysis identified MET protein as an independent prognostic factor for overall survival and MST1R protein as an independent prognostic factor for event-free survival. Subgroup analysis according to Ann Arbor stage showed that expressions of MET and MST1R protein have prognostic impact in the advanced stage only. In particular, coexpression of MST1R and MET protein was associated with a better survival outcome than MET or MST1R expression alone or no expression. This study suggests that MET and MST1R are independent prognostic factors in classical cHL, and may allow the identification of a subgroup of cHL patients who require more intensive therapy.

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Proliferation characteristics in pediatric Hodgkin's lymphoma point to a cell cycle arrest in the G1 phase

Cited by 15 publications

References 34 publications

Characterization and Expression of CT45 in Hodgkin's Lymphoma

Characterization and Expression of CT45 in Hodgkin's Lymphoma

Pediatric Hodgkin lymphoma- biomarkers, drugs, and clinical trials for translational science and medicine

MET and MST1R as prognostic factors for classical Hodgkin's lymphoma

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