Ludger Klein-Hitpass

University of Duisburg-Essen, Essen, North Rhine-Westphalia, Germany

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Publications (152)843.7 Total impact

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    ABSTRACT: The pathogenesis of T-cell large granular lymphocytic leukemia (T-LGL) is poorly understood, as STAT3 mutations are the only known frequent genetic lesions. Here, we identified non-synonymous alterations in the TNFAIP3 tumour suppressor gene in 3 of 39 T-LGL. In two cases these were somatic mutations, in one case the somatic origin was likely. A further case harboured a SNP that is a known risk allele for autoimmune diseases and B cell lymphomas. Thus, TNFAIP3 mutations represent recurrent genetic lesions in T-LGL that affect about 8% of cases, likely contributing to deregulated NF-κB activity in this leukemia. This article is protected by copyright. All rights reserved. © 2015 UICC.
    International Journal of Cancer 07/2015; DOI:10.1002/ijc.29697 · 5.01 Impact Factor
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    ABSTRACT: Maintenance of telomere length is a critical hallmark of malignant transformation. While silenced in somatic cells, telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, is frequently overexpressed in malignant cells thereby maintaining their telomere length. Specific point mutations in the TERT promoter region have recently been identified in melanoma and other tumor entities resulting in high TERT expression. Neuroblastoma is the most common extracranial tumor of childhood, arising from neural-crest progenitor cells. TERT overexpression has been observed in the majority of neuroblastoma. Taking into consideration that TERT promoter mutations are frequently described in neural-crest-derived tumors such as melanoma, as well as a variety of other neuronal tumors, the present study analyzed the frequency of TERT promoter mutations in primary neuroblastoma and neuroblastoma cell lines. In 131 neuroblastoma primary tumors representing the whole spectrum of neuroblastoma, no TERT promoter mutations were detected. However, in 3 out of 19 neuroblastoma cell lines the previously described C228T TERT promoter mutation was present. In conclusion, the TERT promoter mutations are not a frequent mechanism of TERT overexpression in neuroblastoma.
    07/2015; 3(4):443-446. DOI:10.3892/br.2015.463
  • Yu Li · Jan Dürig · Maria Göbel · Maher Hanoun · Ludger Klein-Hitpaß · Ulrich Dührsen
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    ABSTRACT: In bone marrow malignancies, little is known about the fate of stromal cells after replacement of normal cells by neoplastic hematopoietic ones. In this study, fibroblasts from patients with acute myeloid leukemia or myelodysplastic syndromes exhibited a significantly lower ability to support hematopoiesis originating from co-cultured allogeneic CD34-positive cells than did fibroblasts from healthy marrow. Conversely, macrophages from acute myeloid leukemia marrow significantly enhanced the production of blood cells compared with control macrophages. Aberrant function was associated with consistent changes in the expression of genes involved in hematopoietic stem cell control, such as cytokines and regulators of the Wnt signaling pathway.
    International journal of hematology 06/2015; DOI:10.1007/s12185-015-1833-x · 1.68 Impact Factor
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    ABSTRACT: The bursa subacromialis (BS) provides the gliding mechanism of the shoulder and regenerates itself after surgical removal. Thus we aimed explore the presence of mesenchymal stem cells (MSCs) within the human adult BS tissue and characterized the BS cells compared to MSCs from bone marrow (BMSCs) on a molecular level. BS cells were isolated by collagenase digest from BS tissues derived from patients with degenerative rotator cuff tears, and BMSCs were recovered by adherent culture from bone-marrow of patients with osteoarthritis of the hip. BS cells and BMSCs were compared upon their potential to proliferate and differentiate along chondrogenic, osteogenic and adipogenic lineages under specific culture conditions. Expression profiles of markers associated with mesenchymal phenotypes were comparatively evaluated by flow cytometry, immunohistochemistry, and whole genome array analyses. BS cells and BMSCs appeared mainly fibroblastic and revealed almost similar surface antigen expression profiles, which was CD44(+), CD73(+), CD90(+), CD105(+), CD106(+), STRO-1(+), CD14(-), CD31(-), CD34(-), CD45(-), CD144(-). Array analyses revealed 1969 genes upregulated and 1184 genes downregulated in BS cells vs. BMSCs, indicating a high level of transcriptome similarity. After 3 weeks of differentiation culture, BS cells and BMSCs showed a similar strong chondrogenic, adipogenic and osteogenic potential, as shown by histological, immunohistochemical and RT-PCR analyses in contrast to the respective negative controls. Our in vitro characterizations show that BS cells fulfill all characteristics of mesenchymal stem cells, and therefore merit further attention for the development of improved therapies for various shoulder pathologies.
    Stem Cell Research & Therapy 06/2015; 6(1):114. DOI:10.1186/s13287-015-0104-3 · 4.63 Impact Factor
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    ABSTRACT: Patients suffering from the rare hereditary disease hypophosphatasia (HPP), which is based on mutations in the ALPL gene, tend to develop central nervous system (CNS) related issues like epileptic seizures and neuropsychiatric illnesses such as anxiety and depression, in addition to well-known problems with the mineralization of bones and teeth. Analyses of the molecular role of tissue-nonspecific alkaline phosphatase (TNAP) in transgenic SH-SY5Y(TNAPhigh) neuroblastoma cells compared to SH-SY5Y(TNAPlow) cells indicate that the enzyme influences, either directly or indirectly, the expression levels of neuronal marker genes like RNA-binding protein, fox-1 homolog 3 (NEUN) and enolase 2, gamma neuronal (NSE) as well as microtubule binding proteins like microtubule-associated protein 2 (MAP2) and microtubule-associated protein tau (TAU) during neurogenic differentiation. Fluorescence staining of SH-SY5Y(TNAPhigh) cells reveals TNAP localization throughout the whole length of the developed projection network and even synapsin Ι co-localization with strong TNAP signals at some spots at least at the early time points of differentiation. Additional immunocytochemical staining shows higher MAP2 expression in SH-SY5Y(TNAPhigh) cells and further a distinct up-regulation of tau and MAP2 in the course of neurogenic differentiation. Interestingly, transgenic SH-SY5Y(TNAPhigh) cells are able to develop longer cellular processes compared to control cells after stimulation with all-trans retinoic acid (RA). Current therapies for HPP prioritize improvement of the bone phenotype. Unraveling the molecular role of TNAP in extraosseous tissues, like in the CNS, will help to improve treatment strategies for HPP patients, but taking this rare disease as a model may also help to dissect TNAP's role in neurodegenerative diseases and even improve future treatment of common pathologies. Copyright © 2015. Published by Elsevier Inc.
    Bone 05/2015; 79. DOI:10.1016/j.bone.2015.05.033 · 4.46 Impact Factor
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    ABSTRACT: Metastatic fibrosarcomas still represent a therapeutic dilemma. Commonly used chemotherapeutic agents such as doxorubicin have been proven effective in fewer than 30% of all cases disseminated of fibrosarcoma. Elderly patients with cardiac disease are not suitable for systemic chemotherapy with doxorubicin. We therefore tested the apoptotic effects of the natural and well-tolerated compound resveratrol on human fibrosarcoma cells (HT1080). Vital, apoptotic and necrotic cells were quantified using flow cytometric analysis. Gene expression was analyzed by RNA microarrays. Application of resveratrol induced apoptotic cell death and significantly reduced proliferation of HT1080 cells. Correspondingly, expression of apoptosis-associated genes was altered in microarray analysis. This in vitro study demonstrates the anticancer activity of resveratrol against human fibrosarcoma cells. These results provide experimental support for in vivo trials assessing the effect of the natural polyphenol resveratrol. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
    Anticancer research 02/2015; 35(2):767-74. · 1.87 Impact Factor
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    ABSTRACT: Complete surgical resection with clear margins remains the mainstay of therapy for localised fibrosarcomas. Nevertheless, metastatic fibrosarcomas still represent a therapeutic dilemma. Commonly used chemotherapeutic agents like doxorubicin have proven to be effective in <30% of all cases of disseminated fibrosarcoma. Especially elderly patients with cardiac subdisease are not suitable for systemic chemotherapy with doxorubicin. Therefore we tested the apoptotic effects of the well‑tolerated pine bark extract pycnogenol and its constituents on human fibrosarcoma cells (HT1080). Ten healthy subjects (six females, four males, mean age 24.8±6 years) received a single dose of 300 mg pycnogenol orally. Blood plasma samples were obtained before and 6 h after intake of pycnogenol. HT1080 cells were treated with these plasma samples. Additionally, HT1080 were incubated separately with catechin, epicatechin and taxifolin that are known as the main constituents of pycnogenol. Vital, apoptotic and necrotic cells were quantified using flow cytometric analysis. Gene expression was analyzed by RNA microarray. The results showed that single application of taxifolin, catechin and epicatechin reduced cell viability of HT1080 cells only moderately. A single dose of 300 mg pycnogenol given to 10 healthy adults produced plasma samples that led to significant apoptotic cell death ex vivo whereas pycnogenol‑negative serum displayed no apoptotic activity. Microarray analysis revealed remarkable expression changes induced by pycnogenol in a variety of genes, which are involved in different apoptotic pathways of cancer cells [Janus kinase 1 (JAK1), DUSP1, RHOA, laminin γ1 (LAMC1), fibronectin 1 (FN1), catenin α1 (CTNNA1), ITGB1]. In conclusion, metabolised pycnogenol induces apoptosis in human fibrosarcoma cells. Pycnogenol exhibits its pro‑apoptotic activity as a mixture and is more effective than its main constituents catechin, epicatechin and taxifolin indicating that the metabolised components interact synergistically. These results provide experimental support for in vivo trials assessing the effect of the pine bark extract pycnogenol.
    International Journal of Oncology 01/2015; 46(4). DOI:10.3892/ijo.2015.2854 · 3.03 Impact Factor
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    ABSTRACT: Choroid plexus tumors are rare neoplasms that mainly affect children. They include papillomas, atypical papillomas, and carcinomas. Detailed genetic studies are rare, and information about their molecular pathogenesis is limited. Molecular inversion probe analysis is a hybridization-based method that represents a reliable tool for the analysis of highly fragmented formalin-fixed paraffin-embedded tissue-derived DNA. Here, analysis of 62 cases showed frequent hyperdiploidy in papillomas and atypical papillomas that appeared very similar in their cytogenetic profiles. In contrast, carcinomas showed mainly losses of chromosomes. Besides recurrent focal chromosomal gains common to all choroid plexus tumors, including chromosome 14q21-q22 (harboring OTX2), chromosome 7q22 (LAMB1), and chromosome 9q21.12 (TRPM3), Genomic Identification of Significant Targets in Cancer analysis uncovered focal alterations specific for papillomas and atypical papillomas (e.g. 7p21.3 [ARL4A]) and for carcinomas (16p13.3 [RBFOX1] and 6p21 [POLH, GTPBP2, RSPH9, and VEGFA]). Additional RNA expression profiling and gene set enrichment analysis revealed greater expression of cell cycle-related genes in atypical papillomas in comparison with that in papillomas. These findings suggest that atypical papillomas represent an immature variant of papillomas characterized by increased proliferative activity, whereas carcinomas seem to represent a genetically distinct tumor group.
    Journal of Neuropathology and Experimental Neurology 01/2015; 74(2). DOI:10.1097/NEN.0000000000000154 · 4.37 Impact Factor
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    ABSTRACT: Hairy cell leukemia (HCL) shows unique clinico-pathological and biological features. HCL responds well to purine analogues but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF-MEK-ERK pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (Vemurafenib; Dabrafenib) or MEK (Trametinib) inhibitors. Results were validated in vivo in samples from Vemurafenib-treated HCL patients within a phase-2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, TRAP and cyclin-D1, smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by co-culture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and MEK inhibitors in HCL. Copyright © 2014 American Society of Hematology.
    Blood 12/2014; 125(8). DOI:10.1182/blood-2014-10-603100 · 10.43 Impact Factor
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    ABSTRACT: WNT-induced secreted protein 1 (WISP1/CCN4), a member of the CCN protein family, acts as a downstream factor of the canonical WNT signaling pathway. Its expression is known to affect proliferation and differentiation of human mesenchymal stromal cells (hMSCs), which are fundamental for the development and maintenance of the musculoskeletal system. Whereas a dysregulated, excessive expression of WISP1 often reflects its oncogenic potential via the inhibition of apoptosis, our study emphasizes the importance of WISP1 signaling for the survival of primary human cells. We have established the efficient and specific down-regulation of endogenous WISP1 transcripts by gene silencing in hMSCs and observed cell death as a consequence of WISP1 deficiency. This was confirmed by Annexin V staining for apoptotic cells. DNA microarray analyses of WISP1 down-regulated versus control samples revealed several clusters of differentially expressed genes important for apoptosis induction such as TNF-related apoptosis-inducing ligand 1 (TRAIL) and the corresponding apoptosis-inducing receptors TRAIL-R1 and -R2. An increased expression of TRAIL and its receptors TRAIL-R1 and -R2 in WISP1-deficient hMSCs was confirmed by immunocytofluorescence. Accordingly, WISP1 deficiency is likely to cause TRAIL-induced apoptosis. This is an important novel finding, which suggests that WISP1 is indispensable for the protection of healthy hMSCs against TRAIL-induced apoptosis.
    Gene 09/2014; 551(2). DOI:10.1016/j.gene.2014.09.002 · 2.08 Impact Factor
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    ABSTRACT: Neuroblastoma, a childhood cancer that originates from neural crest-derived cells, is the most common deadly solid tumor of infancy. Amplification of the MYCN oncogene, which occurs in approximately 20-25% of human neuroblastomas, is the most prominent genetic marker of high-stage disease. The availability of valid preclinical in vivo models is a prerequisite to develop novel targeted therapies. We here report on the generation of transgenic mice with Cre-conditional induction of MYCN in dopamine β-hydroxylase-expressing cells, termed LSL-MYCN;Dbh-iCre. These mice develop neuroblastic tumors with an incidence of >75%, regardless of strain background. Molecular profiling of tumors revealed upregulation of the MYCN-dependent miR-17-92 cluster as well as expression of neuroblastoma marker genes, including tyrosine hydroxylase and the neural cell adhesion molecule 1. Gene set enrichment analyses demonstrated significant correlation with MYC-associated expression patterns. Array comparative genome hybridization showed that chromosomal aberrations in LSL-MYCN;Dbh-iCre tumors were syntenic to those observed in human neuroblastomas. Treatment of a cell line established from a tumor derived from a LSL-MYCN;Dbh-iCre mouse with JQ1 or MLN8237 reduced cell viability and demonstrated oncogene addiction to MYCN. Here we report establishment of the first Cre-conditional human MYCN-driven mouse model for neuroblastoma that closely recapitulates the human disease with respect to tumor localization, histology, marker expression and genomic make up. This mouse model is a valuable tool for further functional studies and to assess the effect of targeted therapies.Oncogene advance online publication, 1 September 2014; doi:10.1038/onc.2014.269.
    Oncogene 09/2014; DOI:10.1038/onc.2014.269 · 8.56 Impact Factor
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    Peritoneal dialysis international: journal of the International Society for Peritoneal Dialysis 07/2014; 35(3). DOI:10.3747/pdi.2013.00010 · 2.20 Impact Factor
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    ABSTRACT: The canonical Wnt/β-catenin pathway plays a key role in the regulation of bone remodeling in mice and humans. Two transmembrane proteins that are involved in decreasing the activity of this pathway by binding to extracellular antagonists, such as Dickkopf 1 (Dkk1), are the low-density lipoprotein receptor related protein 5 (Lrp5) and Kremen 2 (Krm2). Lrp 5 deficiency (Lrp5-/-) as well as osteoblast-specific overexpression of Krm2 in mice (Col1a1-Krm2) result in severe osteoporosis occurring at young age. In this study, we analyzed the influence of Lrp5 deficiency and osteoblast-specific overexpression of Krm2 on fracture healing in mice using flexible and semi-rigid fracture fixation. We demonstrated that fracture healing was highly impaired in both mouse genotypes, but that impairment was more severe in Col1a1-Krm2 than in Lrp5-/- mice and particularly evident in mice in which the more flexible fixation was used. Bone formation was more reduced in Col1a1-Krm2 than in Lrp5-/- mice, whereas osteoclast number was similarly increased in both genotypes in comparison with wild-type mice. Using microarray analysis we identified reduced expression of genes mainly involved in osteogenesis that seemed to be responsible for the observed stronger impairment of healing in Col1a1-Krm2 mice. In line with these findings, we detected decreased expression of sphingomyelin phosphodiesterase 3 (Smpd3) and less active β-catenin in the calli of Col1a1-Krm2 mice. Since Krm2 seems to play a significant role in regulating bone formation during fracture healing, antagonizing KRM2 might be a therapeutic option to improve fracture healing under compromised conditions, such as osteoporosis.
    PLoS ONE 07/2014; 9(7):e103250. DOI:10.1371/journal.pone.0103250 · 3.23 Impact Factor
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    ABSTRACT: Imprinting of the human RB1 gene is due to the presence of a differentially methylated CpG island (CGI) in intron 2, which is part of a retrocopy derived from the PPP1R26 gene on chromosome 9. The murine Rb1 gene does not have this retrocopy and is not imprinted. We have investigated whether the RB1/Rb1 locus is unique with respect to these differences. For this we have compared the CGIs from human and mouse by in silico analyses. We have found that the human genome does not only contain more CGIs than the mouse, but the proportion of intronic CGIs is also higher (7.7% versa 3.5%). At least 2033 human intronic CGIs are not present in the mouse. Among these CGIs, 104 show sequence similarities elsewhere in the human genome, which suggests that they arose from retrotransposition. We could narrow down the time points when most of these CGIs appeared during evolution. Their methylation status was analysed in two monocyte methylome datasets from whole genome bisulfite sequencing and in 18 published methylomes. Four CGIs, which are located in the RB1, ASRGL1, PARP11 and PDXDC1 genes, occur as methylated and unmethylated copies. In contrast to imprinted methylation at the RB1 locus, differential methylation of the ASRGL1 and PDXDC1 CGIs appears to be sequence-dependent. Our study supports the notion that the epigenetic fate of the retrotransposed DNA depends on its sequence and selective forces at the integration site.
    Genome Biology and Evolution 06/2014; 6(7). DOI:10.1093/gbe/evu125 · 4.53 Impact Factor
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    ABSTRACT: It has been shown previously that aminocoumarin antibiotics such as novobiocin lead to immediate downregulation of recA expression and thereby inhibit the SOS response, mutation frequency and recombination capacity in Staphylococcus aureus. Aminocoumarins function by inhibiting the ATPase activity of DNA gyrase subunit B with a severe impact on DNA supercoiling. Here, we have analysed the global impact of the DNA relaxing agent novobiocin on gene expression in S. aureus. Using a novobiocin-resistant mutant, it became evident that the change in recA expression is due to gyrase inhibition. Microarray analysis and northern blot hybridisation revealed that the expression levels of a distinct set of genes were increased (e.g., recF-gyrB-gyrA, the rib operon and the ure operon) or decreased (e.g., arlRS, recA, lukA, hlgC and fnbA) by novobiocin. The two-component ArlRS system was previously found to decrease the level of supercoiling in S. aureus. Thus, downregulation of arlRS might partially compensate for the relaxing effect of novobiocin. Global analysis and gene mapping of supercoiling-sensitive genes did not provide any indication that they are clustered in the genome. Promoter fusion assays confirmed that the responsiveness of a given gene is intrinsic to the promoter region but independent of the chromosomal location. The results indicate that the molecular properties of a given promoter, rather than the chromosomal topology, dictate the responsiveness to changes in supercoiling in the pathogen Staphylococcus aureus.
    BMC Genomics 04/2014; 15(1):291. DOI:10.1186/1471-2164-15-291 · 4.04 Impact Factor
  • Acta Neuropathologica 02/2014; 127(4). DOI:10.1007/s00401-014-1264-4 · 10.76 Impact Factor
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    ABSTRACT: Ischemic postconditioning (PoCo) reduces infarct size following myocardial ischemia/reperfusion. To protect, PoCo must be performed early during reperfusion, and causal cardioprotective signaling must occur then. The role of microRNA (miRNA) in PoCo is unclear. Anesthetized pigs were subjected to 60 min left anterior descending coronary artery (LAD) occlusion and 180 min reperfusion. Immediate full reperfusion (IFR, n = 5) was compared to PoCo (four cycles of 60 s/60 s reperfusion/reocclusion, n = 5). Transmural myocardial biopsies from the LAD territory were sampled at baseline, 60 min ischemia, 10 and 180 min reperfusion. RNA was isolated. The expression of 11 miRNAs, including muscle-specific (miRNA-1, -133a, -206, -208b, -214, and -499), fibrosis- (miRNA-21, -24, and -29b), neovascularization- (miRNA-92a), and inflammation-associated (miRNA-146b) candidates, was quantified using real-time PCR (RT-PCR). mRNA expression at baseline and 180 min reperfusion was quantified and validated (microarray and RT-PCR). PoCo reduced infarct size from 44.9 ± 7.7 to 34.8 ± 5.3 % of the area at risk. The expression of miRNA-1, -24, -29b, -133a, -146b, -208b, and -499 was increased at 10 min reperfusion with PoCo vs. IFR; however, that of miRNA-1, -24, -208b, and -499 was already increased at 60 min ischemia and probably reflects falsely positive results. Five mRNAs were different with PoCo vs. IFR. In silico analysis identified a tentative connection between three miRNAs and five mRNAs with the biological functions "cell death", "inflammatory response" and/or "glucose metabolism". If at all, only miRNA-29b, -133a, and -146b fulfill the minimal temporal requirements for a potential causal involvement in cardioprotection by PoCo.
    Pflügers Archiv - European Journal of Physiology 01/2014; 466(10). DOI:10.1007/s00424-013-1429-3 · 4.10 Impact Factor
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    ABSTRACT: The fusion between human tumorigenic cells and normal human diploid fibroblasts results in non-tumorigenic hybrid cells, suggesting a dominant role for tumor suppressor genes in the generated hybrid cells. After long-term cultivation in vitro, tumorigenic segregants may arise. The loss of tumor suppressor genes on chromosome 11q13 has been postulated to be involved in the induction of the tumorigenic phenotype of human papillomavirus (HPV)18-positive cervical carcinoma cells and their derived tumorigenic hybrid cells after subcutaneous injection in immunocompromised mice. The aim of this study was the identification of novel cellular genes that may contribute to the suppression of the tumorigenic phenotype of non-tumorigenic hybrid cells in vivo. We used cDNA microarray technology to identify differentially expressed cellular genes in tumorigenic HPV18-positive hybrid and parental HeLa cells compared to non-tumorigenic HPV18-positive hybrid cells. We detected several as yet unknown cellular genes that play a role in cell differentiation, cell cycle progression, cell-cell communication, metastasis formation, angiogenesis, antigen presentation, and immune response. Apart from the known differentially expressed genes on 11q13 (e.g., phosphofurin acidic cluster sorting protein 1 (PACS1) and FOS ligand 1 (FOSL1 or Fra-1)), we detected novel differentially expressed cellular genes located within the tumor suppressor gene region (e.g., EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2) and leucine rich repeat containing 32 (LRRC32) (also known as glycoprotein-A repetitions predominant (GARP)) that may have potential tumor suppressor functions in this model system of non-tumorigenic and tumorigenic HeLa x fibroblast hybrid cells.
    Cancer Genetics 09/2013; DOI:10.1016/j.cancergen.2013.06.002 · 2.42 Impact Factor
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    ABSTRACT: Altered numbers and functions of T cells have previously been demonstrated in chronic lymphocytic leukemia (CLL) patients. However, dynamics and specific T-cell subset alterations have not been studied in great detail. Therefore, we studied CLL blood lymphocyte subsets of individual patients in a longitudinal manner. Dynamic expansions of blood CD4 (+) and CD8 (+) T-cell numbers were consistently associated with a progressively increasing CLL leukemic compartment. Interestingly, the T-cell subset expansion over time was more pronounced in CD38 (+) CLL. Additionally, we performed gene expression profiling of CD3 (+) T cells of CLL patients and normal donors. Using gene set enrichment analysis, we found significant enrichment of genes with higher expression in CLL T cells within CD8(+) effector memory and terminal effector T-cell gene signatures. In agreement with these data, we observed a marked expansion of phenotypic CD8 (+) effector memory T cells in CLL by flow cytometry. Moreover, we observed that increments of CD8 (+) effector memory T cells in human CLL and also mouse CLL (Eμ-TCL1 model) were due to an expansion of the inhibitory killer cell lectin-like receptor G1 (KLRG1) expressing cellular subset. Furthermore, higher plasma levels of the natural KLRG1 ligand E-cadherin were detected in CLL patients compared to normal donor controls. The predominance of KLRG1(+) expression within CD8(+) T cells in conjunction with increased systemic soluble E-cadherin might significantly contribute to CLL immune dysfunction and might additionally represent an important component of the CLL microenvironment.
    Cancer Immunology and Immunotherapy 09/2013; DOI:10.1007/s00262-013-1473-z · 3.94 Impact Factor
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    ABSTRACT: Progranulin (Pgrn) is a 88 kDa secreted protein with pleiotropic functions including regulation of cell cycle progression, cell motility, wound repair and tumorigenesis. Using microarray based gene expression profiling we have recently demonstrated that the gene for Pgrn, granulin (GRN), is significantly higher expressed in aggressive CD38(+)ZAP-70(+) as compared to indolent CD38(-)ZAP-70(-) chronic lymphocytic leukemia (CLL) cases. Here, we measured Pgrn plasma concentrations by enzyme-linked immunosorbent assay (ELISA) in the Essen CLL cohort of 131 patients and examined Pgrn for association with established prognostic markers and clinical outcome. We found that high Pgrn plasma levels were strongly associated with adverse risk factors including unmutated IGHV status, expression of CD38 and ZAP-70, poor risk cytogenetics (11q-, 17p-) as detected by flourescence in situ hybridization (FISH) and high Binet stage. Pgrn as well as the aforementioned risk factors were prognostic for time to first treatment and overall survival in this series. Importantly, these results could be confirmed in the independent multicentric CLL1 cohort of untreated Binet stage A patients (n = 163). Here, multivariate analysis of time to first treatment revealed that high risk Pgrn (HR = 2.06, 95%-CI = 1.13-3.76, p = 0.018), unmutated IGHV status (HR = 5.63, 95%-CI = 3.05-10.38, p<0.001), high risk as defined by the study protocol (HR = 2.06, 95%-CI = 1.09-3.89, p = 0.026) but not poor risk cytogenetics were independent prognostic markers. In summary our results suggest that Pgrn is a novel, robust and independent prognostic marker in CLL that can be easily measured by ELISA.
    PLoS ONE 08/2013; 8(8):e72107. DOI:10.1371/journal.pone.0072107 · 3.23 Impact Factor

Publication Stats

5k Citations
843.70 Total Impact Points

Institutions

  • 2004–2015
    • University of Duisburg-Essen
      • Faculty of Medicine
      Essen, North Rhine-Westphalia, Germany
  • 1994–2014
    • University Hospital Essen
      • • Institute of Pathophysiology
      • • Institute of Cell Biology (Tumor Research)
      • • Institute of Anatomy
      Essen, North Rhine-Westphalia, Germany
  • 2011
    • Institut de recherches cliniques de Montréal
      Montréal, Quebec, Canada
  • 2008–2011
    • IFZ Graz
      Gratz, Styria, Austria
  • 2009
    • Max Planck Institute of Molecular Physiology
      Dortmund, North Rhine-Westphalia, Germany
  • 2008–2009
    • Katholisches Klinikum Essen
      Essen, North Rhine-Westphalia, Germany
  • 2005
    • Universitätsklinikum Erlangen
      • Department of Surgery
      Erlangen, Bavaria, Germany
  • 1989–1990
    • Baylor College of Medicine
      • Department of Molecular & Cellular Biology
      Houston, Texas, United States