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J C Becker,
C Müller-Tidow,
M Stolte,
T Fujimori, N Tidow,
A M Ilea,
C Brandts,
L Tickenbrock,
H Serve,
W E Berdel,
W Domschke,
T Pohle
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ABSTRACT: The epidermal growth factor receptor (EGFR) is highly expressed in gastric cancer indicating its suitability as a target for receptor tyrosine kinase (RTK) inhibitors. In the current study we explored the role of EGFR and its potential use as a therapeutic target in gastric cancer. First we analyzed 66 gastric cancer samples of Asian and Caucasian patients for the presence of EGFR mutations. No activating EGFR mutations were found and gefitinib alone was only weakly effective in gastric cancer cell lines. However, acetylsalicylic acid (ASA) significantly enhanced the inhibitory effects of gefitinib indicating synergistic action. Whole genome expression profiling indicated significant regulation of 120 genes in the case of co-administration of gefitinib and ASA (32 induced, 88 repressed) in gastric adenocarcinoma cells. Further analyses indicated that several important signalling pathways were effectively inhibited by simultaneous exposure to gefitinib and ASA. Our findings indicate that although gastric cancer does not seem to harbour mutations which render the cancer cells constitutively susceptible to gefitinib, the co-administration of ASA can strengthen RTK inhibitor activity in adenocarcinoma cells by EGFR activation. This is the first report of effective modulation of EGFR-inhibition activity in cancer.
International Journal of Oncology 10/2006; 29(3):615-23. · 2.40 Impact Factor
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ABSTRACT: To analyse the association of interleukin 10 (IL10) promoter polymorphisms, which have been shown to be related to IL10 secretion capacity, with the response to long term treatment with etanercept in patients with rheumatoid arthritis (RA).
Fifty patients with active RA were treated for up to 4 years (median 39 months, range 3-52) with stable doses of etanercept as monotherapy. Treatment response was assessed as defined by the EULAR criteria in an intention to treat analysis, with the last observation carried forward. IL10 promoter microsatellite polymorphisms IL10.R and IL10.G were genotyped by fragment length analysis in patients and 189 healthy controls matched for ethnicity, age, and sex. Haplotypes were reconstructed using a method based on bayesian, coalescent theory with the PHASE software.
IL10 microsatellite polymorphisms were not associated with susceptibility to RA. When patients with good treatment response (n = 25) were compared with patients with moderate (n = 17) or no response (n = 8), a significantly different distribution of the prevailing alleles R2, R3 and G9, G13, respectively, became evident. Good treatment response was associated with carriage of the R3 allele or R3-G9 haplotype, whereas the allele G13 and the haplotype R2-G13 predominated in patients with moderate or no response.
Genotyping of the IL10 promoter microsatellites may be useful in predicting the clinical response to etanercept in patients with RA. The high prevalence of the presumptive IL10 low producer allele R3 in patients with a favourable response suggests that IL10 promotes disease activity in RA under the specific condition of tumour necrosis factor antagonism.
Annals of the Rheumatic Diseases 05/2005; 64(4):575-81. · 8.73 Impact Factor
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ABSTRACT: Overproduction of interleukin-10 (IL-10) is a pivotal feature in the pathophysiology of systemic lupus erythematosus (SLE). In vitro IL-10 secretion has previously been related to haplotypes of the IL-10 promoter microsatellite polymorphisms IL10.R and IL10.G. Published data concerning the association of IL10.G alleles with susceptibility to SLE are inconsistent in different ethnic populations. We analysed the association of IL-10 promoter microsatellite polymorphisms with disease susceptibility and manifestations in German Caucasian patients with SLE.
Two hundred and ten (210) SLE patients fulfilling the 1997 revised ACR criteria and 158 ethnically, age- and sex-matched healthy controls were genotyped for the IL-10 promoter microsatellite polymorphisms by fragment length analysis. Haplotypes were reconstructed using a Bayesian coalescent theory-based method with PHASE software. Allele and haplotype distributions were compared between patients and controls and between subgroups of patients with different clinical and immunopathological findings.
In the study population no significant associations of individual IL10.R and G alleles or their haplotypes with susceptibility to SLE or major clinical manifestations were observed. By contrast, alleles G14 and G15 and haplotypes R2-G14 and R2-G15 were significantly over-represented in anti-Sm antibody-positive patients.
The IL-10 promoter microsatellite polymorphisms and their haplotypes do not constitute a major risk factor for SLE in German Caucasians. However, the identification of genetic markers such as the IL-10 high-response haplotype R2-G14 predisposing for the production of anti-Sm antibodies may help to elucidate the conditions that lead to the development of SLE.
Rheumatology 12/2004; 43(11):1357-63. · 4.06 Impact Factor
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ABSTRACT: The biological function of pyrin, the protein mutated in Familial Mediterranean Fever (FMF), has not been elucidated. Based on sequence homology, a transcription factor activity was proposed for this neutrophil-specific protein. In a yeast two-hybrid assay, neither transcription activation activity nor any self interaction was detected for pyrin. Screening of an expression cDNA library of peripheral blood leukocytes using as bait the carboxyl portion of pyrin (amino acids 557-781), which contains most of the FMF mutations, led to the identification of P/M-IP1 (pyrin/marenostrin interacting protein 1). A splice variant of P/M-IP1, GTC-90, had previously been described as a component of the 13S hetero-oligomeric protein complex that stimulates in vitro Golgi transport. We have now shown that P/M-IP1 colocalizes with pyrin in the perinuclear cytoplasm of Cos-7 cells and that the interaction between these two proteins is impaired by FMF causing mutations in pyrin. These data suggest that, at some stage of its functional pathway, pyrin resides in the cytoplasm and might be involved in, or impacted by, cellular protein sorting by the Golgi apparatus. The data also imply that P/M-IP1 may be involved in the abnormal inflammatory response that occurs in patients with FMF.
Proceedings of The Society for Experimental Biology and Medicine 06/2000; 224(1):32-40.
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ABSTRACT: Severe congenital neutropenia (SCN) or Kostmann syndrome is a disorder of myelopoiesis characterized by a maturation arrest at the stage of promyelocytes or myelocytes in bone marrow and absolute neutrophil counts less than 200/microL in peripheral blood. Treatment of these patients with granulocyte colony-stimulating factor (G-CSF) leads to a significant increase in circulating neutrophils and a reduction in infection-related events in more than 95% of the patients. To date, little is known regarding the underlying pathomechanism of SCN. G-CSF-induced neutrophils of patients with SCN are functionally defective (eg, chemotaxis, superoxide anion generation, Ca(++ )mobilization). Two guanosine triphosphatases (GTPases), Rac2 and RhoA, were described to be involved in many neutrophil functions. The expression of these GTPases and their regulation in patients' neutrophils were of interest. This study determined that the guanosine diphosphate (GDP)-dissociation inhibitor RhoGDI is overexpressed at the protein level in patients' neutrophils and that overexpression is a result of G-CSF treatment. RhoA and LyGDI are expressed at similar levels, whereas Rac2 shows a decreased expression. In addition, association of Rac2 and RhoGDI or LyGDI is abrogated or not detectable based on the low Rac2 expression in patients' neutrophils. (Blood. 2000;95:2947-2953)
Blood 06/2000; 95(9):2947-53. · 9.90 Impact Factor
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ABSTRACT: Gene expression in mammalian organisms is regulated at multiple levels, including DNA accessibility for transcription factors and chromatin structure. Methylation of CpG dinucleotides is thought to be involved in imprinting and in the pathogenesis of cancer. However, the relevance of methylation for directing tissue-specific gene expression is highly controversial. The cyclin A1 gene is expressed in very few tissues, with high levels restricted to spermatogenesis and leukemic blasts. Here, we show that methylation of the CpG island of the human cyclin A1 promoter was correlated with nonexpression in cell lines, and the methyl-CpG binding protein MeCP2 suppressed transcription from the methylated cyclin A1 promoter. Repression could be relieved by trichostatin A. Silencing of a cyclin A1 promoter-enhanced green fluorescent protein (EGFP) transgene in stable transfected MG63 osteosarcoma cells was also closely associated with de novo promoter methylation. Cyclin A1 could be strongly induced in nonexpressing cell lines by trichostatin A but not by 5-aza-cytidine. The cyclin A1 promoter-EGFP construct directed tissue-specific expression in male germ cells of transgenic mice. Expression in the testes of these mice was independent of promoter methylation, and even strong promoter methylation did not suppress promoter activity. MeCP2 expression was notably absent in EGFP-expressing cells. Transcription from the transgenic cyclin A1 promoter was repressed in most organs outside the testis, even when the promoter was not methylated. These data show the association of methylation with silencing of the cyclin A1 gene in cancer cell lines. However, appropriate tissue-specific repression of the cyclin A1 promoter occurs independently of CpG methylation.
Molecular and Cellular Biology 06/2000; 20(9):3316-29. · 5.53 Impact Factor
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ABSTRACT: Familial Mediterranean fever (FMF) is a recessively inherited disorder characterized by recurrent, self-limited attacks of fever and serositis and by infiltration of affected tissues by large numbers of neutrophils. A candidate gene for FMF was identified by positional cloning and named "MEFV." The corresponding protein was named "pyrin." To elucidate the currently unknown function of pyrin, we characterized its tissue distribution, regulation of expression during hematopoietic differentiation, and subcellular localization. Reverse transcription-polymerase chain reaction analysis, followed by hybridization with an internal oligonucleotide, demonstrated expression of MEFV in different populations of peripheral blood cells. Among hematopoietic cell lines, MEFV was almost exclusively expressed in cells of the myeloid lineage. Furthermore, MEFV messenger RNA was strongly expressed within 24 hours of dimethyl sulfoxide-induced granulocytic differentiation of HL-60 cells. Analysis of complementary DNA from human solid tumor-derived cell lines revealed expression of MEFV in several cell lines derived from colon and prostate cancers. Expression of MEFV fused to enhanced green fluorescent protein showed that pyrin localized in distinct patches in the cytoplasm, forming a perinuclear cap. Taken together, MEFV is predominantly expressed in myeloid cells and upregulated during myeloid differentiation, and the corresponding protein, pyrin, is expressed in the cytoplasm. (Blood. 2000;95:1451-1455)
Blood 03/2000; 95(4):1451-5. · 9.90 Impact Factor
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ABSTRACT: Cyclin A1 differs from other cyclins in its highly restricted expression pattern. Besides its expression during spermatogenesis, cyclin A1 is also expressed in hematopoietic progenitor cells and in acute myeloid leukemia. We investigated mechanisms that might contribute to cyclin A1 expression in hematopoietic cells. Comparison of cyclin A1 and cyclin A promoter activity in adherent and myeloid leukemia cell lines showed that the cyclin A1 promoter is preferentially active in myeloid cell lines. This preferential activity was present in a small, 335-bp cyclin A1 promoter fragment that contained several potential c-myb binding sites. Coexpression of a c-myb expression vector with the cyclin A1 promoter constructs significantly increased the reporter activity in adherent CV-1 as well as in myeloid U937 cells. Gel-shift assays demonstrated that c-myb could bind to the cyclin A1 promoter at a binding site located near the transcription start site. Site-directed mutagenesis of this site decreased promoter transactivation by 50% in both KCL22 cells that express high levels of c-myb and in CV-1 cells that were transfected with c-myb. In addition, transfection of primary human embryonic fibroblasts with a c-myb expression vector led to induction of the endogenous cyclin A1 gene. Taken together, c-myb can directly transactivate the promoter of cyclin A1, and c-myb might be involved in the high-level expression of cyclin A1 observed in acute myeloid leukemia. These findings suggest that c-myb induces hematopoiesis-specific mechanisms of cell cycle regulation.
Blood 01/2000; 94(12):4255-62. · 9.90 Impact Factor
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ABSTRACT: Severe congenital neutropenia (SCN) is characterized by a maturation arrest of myeloid progenitor cells at the stage of promyelocytes in bone marrow and low levels of mature neutrophils in peripheral blood. To date, little is known regarding the underlying pathomechanism of SCN. A defective response of neutrophil precursors to granulocyte colony-stimulating factor (G-CSF) is a suggested mechanism. In the last few years, we and others described point mutations in the cytoplasmic domain of the G-CSF receptor (G-CSFR) mRNA in a subgroup of SCN patients. In one allele of the G-CSFR gene, a C to T substitution resulted in a change from a glutamine codon to a stop codon. The expected G-CSFR proteins were truncated by 83 to 98 amino acids. In this study, we show that the Lyn and Syk kinases are associated with the G-CSFR in neutrophils from SCN patients with point mutations in the cytoplasmic domain of the G-CSFR mRNA. These findings provide additional proof of the expression of normal G-CSFRs in these patients, because the possible Syk binding motif is located between amino acid 727 and 747 in the G-CSFR.
International Journal of Hematology 01/2000; 70(4):241-7. · 1.27 Impact Factor
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ABSTRACT: Severe congenital neutropenia (SCN) or Kostmann's syndrome is characterized by a stop in differentiation of myeloid progenitor cells at the myelocytic or promyelocytic stage. The pathophysiology of SCN is still unclear. We previously showed that the tyrosine kinase JAK2 is phosphorylated and activated in neutrophils from patients with severe congential neutropenia. We investigated the role of tyrosine phosphatases in this disease. Expression of the SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2 was analyzed in myeloid cells from patients with SCN in comparison to healthy donors. We investigated tyrosine phosphatase expression in myeloid cells at the protein level by Western blot analysis using polyclonal antisera against SHP-1 and SHP-2. Whereas SHP-1 and SHP-2 were hardly detectable in neutrophils from healthy donors, neutrophils from patients with SCN revealed high amounts of these two proteins in Western blot analyses. Reverse transcriptase-polymerase chain reaction and Northern blot analyses demonstrated no dramatic differences of SHP-1 mRNA in neutrophils from congenital neutropenia patients as compared to healthy donors. SHP-2 mRNA was hardly detectable in the neutrophils from patients and in normal neutrophils. Increased expression of SHP protein correlated with elevated activity of both SHP-1 and SHP-2 in neutrophils of patients with SCN. Taken together, these data indicate differential regulation for SHP-1 and SHP-2 at the protein level in neutrophils from SCN patients in comparison to healthy donors. We suggest that overexpression of SHP-1 and SHP-2 protein in neutrophils and not in mononuclear cells from patients with SCN might be related to the disease, e.g., by defective dephosphorylation of proteins involved in intracellular signaling pathways.
Experimental Hematology 07/1999; 27(6):1038-45. · 2.90 Impact Factor
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Int J Hematol. 01/1999; 70:241-247.
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Critical Reviews in Oncology/Hematology 07/1998; 28(1):1-6. · 4.41 Impact Factor
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Blood 11/1997; 90(7):2839-41. · 9.90 Impact Factor
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ABSTRACT: Granulocyte colony-stimulating factor (G-CSF) exerts its biologic effects through binding to its receptor expressed on myeloid cells. Like other cytokines, G-CSF induces intracellular protein tyrosine phosphorylation and activates various signaling cascades. Activation of JAK tyrosine kinases and signal transducers and activators of transcription (STAT) proteins as well as activation of the ras-MAP kinase route results in induction of gene transcription. Distinct regions or defined tyrosine residues of the G-CSF receptor cytoplasmic domain are required for complex formation with specific signaling molecules and ultimately regulate proliferation and maturation of myeloid cells. In vivo, administration of G-CSF results in increased numbers of neutrophils in normal individuals, in patients with chemotherapy-induced neutropenia, and in patients with chronic neutropenia. A subgroup of patients with severe congenital neutropenia displayed point mutations in the cytoplasmic region of the G-CSF receptor: These G-CSF receptor mutations might be involved in leukemogenesis in congenital neutropenia.
Current Opinion in Hematology 06/1997; 4(3):171-5. · 4.52 Impact Factor
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ABSTRACT: Recently, point mutations in the gene of the granulocyte colony-stimulating factor (G-CSF) receptor have been reported in two patients with severe congenital neutropenia who developed acute myeloid leukemia (AML). We investigated the frequency of these specific G-CSF receptor mutations in patients with congenital neutropenia undergoing treatment with r-metHuG-CSF (Filgrastim) and the clinical relevance of these mutations. Nucleotides 2306 to 2561 including the critical region (nucleotides 2384-2429) from the intracellular domain of the G-CSF receptor gene were amplified by reverse transcriptase-polymerase chain reaction. Detection of point mutations was performed with specific restriction enzyme analysis, as well as sequencing of PCR products. Both genomic DNA and cDNA from neutrophils and mononuclear cells were analyzed from 28 patients with severe congenital neutropenia. Four of 28 patients with congenital neutropenia displayed a point mutation in the tested cytoplasmic region of the G-CSF receptor gene. The point mutations replace a glutamine codon by a stop codon of the G-CSF receptor gene. Among these four congenital neutropenia patients with a mutated G-CSF receptor, two developed AML. All four patients were investigated regularly and no correlation between occurrence of G-CSF receptor mutation and time or dose of r-metHuG-CSF treatment was found. No point mutations in the G-CSF receptor critical domain could be detected in cells from the other 24 congenital neutropenia patients. Furthermore, we tested six family members of the two patients with AML including mothers and fathers, one sister, and one brother who suffers from congenital neutropenia, as well. All family members displayed a normal G-CSF receptor gene. After the acquisition of the G-CSF receptor mutations, the congenital neutropenia patients continued to respond to G-CSF therapy with an increase in absolute neutrophils in the peripheral blood. We conclude that the point mutations in the critical region of the intracellular part of the G-CSF receptor occur spontaneously and are not inherited. From our data, we suggest that the described G-CSF receptor point mutations do not alter the response to treatment with r-metHuG-CSF and are not the cause of severe congenital neutropenia.
Blood 05/1997; 89(7):2369-75. · 9.90 Impact Factor
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ABSTRACT: Point mutations in the gene for the G-CSF receptor have been reported previously in a subgroup of patients with severe congenital neutropenia. Here, we investigated the frequency of these specific G-CSF receptor mutations in patients with neutropenic disorders undergoing treatment with recombinant human (r-metHu)G-CSF (Filgrastim). Nucleotides 2306 to 2561, including the critical region (nucleotides 2384-2429) from the intracellular domain of the G-CSF receptor gene, were amplified by reverse transcriptase-polymerase chain reaction, and DNA was sequenced directly and after transformation in E. coli. Four of 30 patients with severe congenital neutropenia displayed a point mutation in the tested cytoplasmic region of the G-CSF receptor gene. Two of the four patients with a mutated G-CSF receptor developed acute myeloid leukemia secondary to congenital neutropenia. G-CSF receptor analyses were performed in myeloid cells taken at different time points in the four patients with the mutated receptor, and no correlation between occurrence of the mutation and time or dose of r-metHuG-CSF treatment was found. No point mutations in the G-CSF receptor critical domain could be detected in cells from the other 26 congenital neutropenia patients. Additionally, no G-CSF receptor point mutations could be seen in neutrophils, blood and bone marrow mononuclear cells from patients with cyclic or idiopathic neutropenia, and bone marrow mononuclear cells from patients suffering from severe aplastic anemia. Similar results were obtained by Touw et al., demonstrating that five out of 25 patients with congenital neutropenia reveal G-CSF receptor mutations. These data show that the point mutations in the critical region of the intracellular part of the G-CSF receptor occur only in a subgroup of severe congenital neutropenia patients. Furthermore, our data suggest that the described G-CSF receptor point mutations are not correlated with the start, duration or doses of r-metHuG-CSF treatment, but might result from genetic instability in the G-CSF receptor gene in severe congenital neutropenia.
Stem Cells 02/1997; 15 Suppl 1:113-9; discussion 120. · 7.78 Impact Factor
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ABSTRACT: Severe congenital neutropenia (SCN; or Kostmann syndrome) is an autosomal recessive disorder characterized by a maturation arrest of myelopoiesis at the level of promyelocytes. Myeloid precursor cells from patients with SCN require pharmacological dosages of recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF; Filgrastim; Amgen, Thousand Oaks, CA) to differentiate to normal neutrophils. Thus, it is hypothesized that the underlying defect responsible for SCN is based on an abnormal G-CSF-induced signal transduction pathway. Because JAK2, a nonreceptor tyrosine kinase, is involved in the signaling pathway of G-CSF, we examined the expression and activity of JAK2 in neutrophils from SCN patients during r-metHuG-CSF treatment. The immunoprecipitated JAK2 protein showed increased tyrosine phosphorylation in neutrophils from SCN patients as compared with that in neutrophils from healthy donors, suggesting that this kinase is activated. In vitro kinase assays of immunoprecipitated JAK2 confirmed that neutrophils from SCN patients show an increased autophosphorylation of JAK2 in comparison with that of neutrophils from healthy volunteers. These findings suggest that JAK2 is activated in SCN patients.
Blood 01/1996; 86(12):4500-5. · 9.90 Impact Factor
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ABSTRACT: In severe congenital neutropenia the maturation of myeloid progenitor cells is arrested. The myelodysplastic syndrome and acute myeloid leukemia develop in some patients with severe congenital neutropenia. Abnormalities in the signal-transduction pathways for granulocyte colony-stimulating factor (G-CSF) may play a part in the progression to acute myeloid leukemia.
We isolated genomic DNA and RNA from hematopoietic cells obtained from two patients with acute myeloid leukemia and histories of severe congenital neutropenia. The nucleotide sequences encoding the cytoplasmic domain of the G-CSF receptor were amplified by means of the polymerase chain reaction and sequenced. Murine myeloid 32D.C10 cells were transfected with complementary DNA encoding the wild-type or mutant G-CSF receptors and tested for their responses to G-CSF.
Point mutations in the gene for the G-CSF receptor were identified in both patients. The mutations, a substitution of thymine for cytosine at the codon for glutamine at position 718 (Gln718) in one patient and at the codon for glutamine at position 731(Gln731) in the other, caused a truncation of the C-terminal cytoplasmic region of the receptor. Both mutant and wild-type genes for the G-CSF receptor were present in leukemic cells from the two patients. In one patient, the mutation was also found in the neutropenic stage, before the progression to acute myeloid leukemia. The 32D.C10 cells expressing mutant receptors had abnormally high proliferative responses but failed to mature when cultured in G-CSF. The mutant G-CSF receptors also interfered with terminal maturation mediated by the wild-type G-CSF receptor in the 32D.C10 cells that coexpressed the wild-type and mutant receptors.
Mutations in the gene for the G-CSF receptor that interrupt signals required for the maturation of myeloid cells are involved in the pathogenesis of severe congenital neutropenia and associated with the progression to acute myeloid leukemia.
New England Journal of Medicine 09/1995; 333(8):487-93. · 53.30 Impact Factor
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ABSTRACT: To study the relative contribution of tumour necrosis factor (TNF) and HLA-DRB1 polymorphisms to the genetic susceptibility to systemic lupus erythematosus (SLE) via an extended haplotype analysis.
We performed an association study in 205 unrelated German Caucasian patients with SLE fulfilling the 1997 revised American College of Rheumatology (ACR) criteria. Healthy age-, ethnically- and sex-matched individuals (n = 157) served as controls. HLA-DRB1 typing was performed by a sequence-specific oligonucleotide hybridisation assay. Two TNF single nucleotide polymorphisms (SNPs) and two multiallelic microsatellites were analysed by mutagenically separated polymerase chain reaction (PCR) or fragment length analysis, respectively. Extended haplotypes were reconstructed with the PHASE software.
Alleles for all polymorphic loci studied and the most frequent haplotypes showed a significantly different distribution between SLE patients and controls. The alleles HLA-DR2, DR3, TNFd1, TNF2, TNFB*1, and TNFa2, designated as risk alleles, and the extended haplotypes DR3-TNFd1-TNF2-TNFB*1-TNFa2 and DR2-TNFd3-TNF1-TNFB*2-TNFa11 prevailed in SLE patients. TNF risk alleles were strongly positively linked with HLA-DR3 and negatively linked with HLA-DR2. Thus, in HLA-DR3 haplotypes individual effects of TNF polymorphisms could not be resolved. By contrast, HLA-DR2 showed an association with SLE independently of TNF risk alleles, while the risk increased further when they were present. In haplotypes lacking HLA-DR2 and DR3, the alleles TNFdl and TNF2 contributed independently to SLE susceptibility.
Extended haplotype analysis revealed HLA-DR3 independent associations of TNF polymorphisms with susceptibility to SLE. Haplotypes that have been shown to be associated with different TNF-alpha production capacity may prevail in different disease subgroups.
Scandinavian Journal of Rheumatology 34(2):114-21. · 2.47 Impact Factor
