Biomedical subjects
Publications and source records attributed to H Van Den Berghe.
From cytogenetic and immunohistochemical findings in a primary giant cell fibrosarcoma and its recurrence, it is further demonstrated that a close relationship exists between this tumor and dermatofibrosarcoma protuberans. Both tumors express CD34 and show rearrangements of chromosomes 17 and 22.
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A structural change of chromosome 1 in q12 may be a new, possibly consistent, chromosome change in adenocarcinoma of the prostate.
We report three cases of myeloid disorders with a dic(1;15)(p11;p11), resulting in trisomy of the long arm of chromosome 1. A review of the literature showed six cases, reported as t(1;15). We suggest that these cases have the same anomaly and should be reappraised as dic(1;15).
Cytogenetic investigations have already shown the nonrandom involvement of region 1p11-p13 in the localized and diffuse forms of tenosynovial giant cell tumors. We describe a new case of modular tenosynovitis with rearrangement of 16q24. Our findings and the data from the literature strongly indicated band 16q24 as an important new breakpoint for the localized as well as diffuse forms of tenosynovial giant cell tumors.
A review of the literature reveals numerous clinical case reports, systematic histologic analyses, epidemiologic studies, and large series of tumors showing that subjects with trisomy 8, 9, 13, 18, and 21 have an excess of hematologic and various solid tumors compared to the general population. These tumors more frequently affect particular organs for a given type of trisomy. A large proportion of tumors are observed during fetal and neonatal life, are incompletely developed, and subsequently regress. In older children or even adults, tumors are less frequent, are often found on the same organs as earlier in life, are more aggressive, and do not involute. The mechanism responsible for the development of these neoplasms could be similar to that which generates the malformations in these children and may result from cooperation of the chromosomal abnormality with physiologic growth phenomena, which are particularly active early in life. Trisomic subjects must be carefully followed in order to detect tumors as early as possible and to allow treatment under optimal conditions.
The formation of distinctive basic FGF-heparan sulfate complexes is essential for the binding of bFGF to its cognate receptor. In previous experiments, cell-surface heparan sulfate proteoglycans extracted from human lung fibroblasts could not be shown to promote high affinity binding of bFGF when added to heparan sulfate-deficient cells that express FGF receptor-1 (FGFR1) (Aviezer, D., D. Hecht, M. Safran, M. Eisinger, G. David, and A. Yayon. 1994. Cell 79:1005-1013). In alternative tests to establish whether cell-surface proteoglycans can support the formation of the required complexes, K562 cells were first transfected with the IIIc splice variant of FGFR1 and then transfected with constructs coding for either syndecan-1, syndecan-2, syndecan-4 or glypican, or with an antisense syndecan-4 construct. Cells cotransfected with receptor and proteoglycan showed a two- to three- fold increase in neutral salt-resistant specific 125I-bFGF binding in comparison to cells transfected with only receptor or cells cotransfected with receptor and anti-syndecan-4. Exogenous heparin enhanced the specific binding and affinity cross-linking of 125I-bFGF to FGFR1 in receptor transfectants that were not cotransfected with proteoglycan, but had no effect on this binding and decreased the yield of bFGFR cross-links in cells that were cotransfected with proteoglycan. Receptor-transfectant cells showed a decrease in glycophorin A expression when exposed to bFGF. This suppression was dose-dependent and obtained at significantly lower concentrations of bFGF in proteoglycan-cotransfected cells. Finally, complementary cell-free binding assays indicated that the affinity of 125I-bFGF for an immobilized FGFR1 ectodomain was increased threefold when the syndecan-4 ectodomain was coimmobilized with receptor. Equimolar amounts of soluble syndecan-4 ectodomain, in contrast, had no effect on this binding. We conclude that, at least in K562 cells, syndecans and glypican can support bFGF-FGFR1 interactions and signaling, and that cell-surface association may augment their effectiveness.
Intrachromosomal telomeric sequences (TTAGGG)n were analyzed in the two members of the family Giraffidae, the giraffe and the okapi. The giraffe has a diploid chromosome number of 2n = 30, whereas the okapi chromosome number varies from 2n = 46 to 2n = 45 and 2n = 44 due to a "recent" Robertsonian fusion event. The interstitial telomeres that we detected in these species are of two types: (1) In the okapi, a long interstitial telomeric element is present at the fusion site of the rob(4;26). The nature of this interstitial telomeric element suggests that it is a remnant of the telomeres of the ancestral chromosomes that participated in the fusion event. (2) In the giraffe, short stretches or degenerate telomeric sequences which are part of the satellite DNA are present at intrachromosomal sites. The results of this study provide insights into the origin of interstitial telomeric sequences in the Giraffidae.
Two new cases of t(8;16)(p11;p13) in acute nonlymphocytic leukemia (ANLL) are described. These two patients in addition to the 34 previously described, showed a striking association with myelomonocytic (M4) or monocytic (M5) leukemia, extramedullary infiltration, erythrophagocytosis and disseminated intravascular coagulation. One of our patients showed a TCRbeta gene rearrangement. Alltogether 36 cases of t(8;16) ANLL have been documented until today. We here review their clinical and cytogenetic features.
Secretory processing and polarized sorting of horseradish peroxidase fused to the amyloid precursor protein transmembrane domain were compared with those of wild-type amyloid precursor protein in COS and polarized Madin-Darby canine kidney (MDCK) cells. The cellular and secreted forms of the chimeric protein were enzymatically active in colorimetric and cytochemical assays after reconstitution with hemin and Ca2+. The peroxidase enzyme was secreted by a proteolytic process, similar to the parent amyloid precursor protein. In polarized MDCK cells, amyloid precursor protein was secreted exclusively in the basolateral compartment, while the peroxidase chimeric protein was secreted in both compartments. The basolateral sorting determinant for secretion must therefore be located in the extracellular domain of amyloid precursor protein. On the other hand, cell surface-associated peroxidase chimeric protein was similar to cell surface-associated wild-type amyloid precursor protein, mainly expressed at the basolateral side. The basolateral cell-surface expression, in contrast to the basolateral secretion, is therefore controlled by determinants in the cytoplasmic domain. Methylamine inhibited and bafilomycin slightly increased the basolateral secretion of both proteins, but both drugs strongly increased apical secretion. The default secretory pathway of COS cells and the basolateral (but not the apical) secretory pathway of MDCK cells are therefore comparably sensitive to methylamine and not to bafilomycin.
We have constructed a physical map of a 4.6-cM region of human chromosome band 12p13.3 that contains a translocation breakpoint from a mesothelioma with a t(X;12)(q22;p13). The map contains a contig of 22 yeast artificial chromosomes (YACs), onto which we have placed 18 sequence tagged site (STS) markers, including seven genes: D12S370, FGF6, KCAN1, KCNA5, KCNA6, NTF3, and VWF. A second YAC contig, comprised of 22 YAC clones, was located distal to the mesothelioma breakpoint and contained 12 STS markers, including four genes (CACNL1A1, D12S380E, D12S381E, and D12S382E). Based on STS content and fluorescence in situ hybridization experiments, two stable, nonchimeric YAC clones were found that span the mesothelioma breakpoint. A long-range restriction map of an 800-kb region was constructed and used to refine the mesothelioma breakpoint to a region of approximately 100 kb, flanked by the potassium channel genes KCNA1 and KCNA5. The latter was confirmed by direct visual hybridization (DIRVISH) experiments, using cosmids isolated for markers flanking the breakpoint as probes.
Cytogenetic and fluorescence in situ hybridization (FISH) studies on a t(14;18)-positive follicular lymphoma presenting a remarkable pattern of secondary chromosomal changes are reported. Chromosome analysis of a lymph node biopsy performed at diagnosis revealed the presence of four related subclones characterized by the (14;18) translocation alone or together with one of the following anomalies: add(1)(p36), add(13)(q34), or der(12)(12;13)(q24;q14)add(13)(q34). The chromosome 9 origin of the extra material on the abnormal chromosomes 1 and 13 was demonstrated by FISH and points to "jumping" translocation in the present case.
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Amyloid precursor protein (APP) secretase plays a pivotal role in the processing of APP since its activity precludes the formation of amyloid peptide in Alzheimer's Disease. The identity and the subcellular localization of this enzyme are at this moment unknown. It is also unclear how APP escapes the activity of this enzyme when amyloid is formed. We have previously shown that APP-secretase activity is not inhibited by exogenously added proteinase inhibitors of different specificity (De Strooper, B., F. Van Leuven, and H. Van Den Berghe. 1992. FEBS (Fed. Eur. Biochem. Soc.) Lett. 308:50-53). We show here that the primary amine methylamine inhibits the secretion of APP into the medium. Furthermore, we show that a truncated form of APP, devoid of the cytoplasmic domain, is more efficiently cleaved and secreted than wild-type APP, which together with the methylamine block, shows that APP-secretase is located in a late compartment of the default constitutional secretion pathway. The sorting signals in the cytoplasmic domain of APP are therefore important in the deviation of APP from the secretase pathway. Finally we show that mutation of Arg609 to Asp in combination with Lys612 to Glu makes APP a less efficiently cleaved substrate for APP-secretase. The results are discussed in the context of recent findings on the targeting of APP and a parallel is drawn with some lysosomal glycoproteins that follow similar pathways.
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Cytogenetic analysis of a rare adipose tissue tumor, hibernoma, a benign proliferation of the brown fat, is presented for the first time. A complex translocation involving bands 1p36, 2q33, 5q22, and 11q13 was found as the sole chromosome abnormality.
An inverted chromosome 6, at bands p21 and q22, has been found as the sole chromosome abnormality in an endometrial polyp from a 50-year-old woman. Since two out of three previously reported endometrial polyps showed a rearrangement of the same band 6p21, the nonrandom involvement of the terminal region of the short arm of chromosome 6 in this benign tumor can be supported.
We report two patients with a myelodysplastic syndrome and the Philadelphia (Ph) chromosome. The first patient was a 73-year-old man who was diagnosed as having a chronic myelomonocytic leukemia in combination with features suggestive of a myeloproliferative syndrome. Chromosomal analysis showed a normal karyotype in the majority of cells, mixed with metaphases containing a standard Ph translocation, t(9;22)(q34;q11), as well as a translocation between chromosome 4 and 6: t(4;6)(p15;p12). Southern blot analysis showed breakpoint cluster region rearrangement as observed in classic chronic myeloid leukemia. The second patient was a 63-year-old man with a myelodysplastic syndrome, type refractory anemia. Cytogenetic study of bone marrow cells at the time of diagnosis revealed a normal karyotype: 46,XY. The initial myelodysplastic syndrome evolved to a myeloproliferative phase with progressive leukocytosis and thrombocytosis. During the terminal phase the Ph chromosome was discovered in 100% of the examined cells. We discuss the correlation between MDS and myeloproliferative diseases, the de novo acquisition of the Ph chromosome during the course of a myelodysplastic syndrome, and review the literature.