Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The consistency of the breakpoint on chromosome 5 at band 5q35 occurring in Ki-1 non-Hodgkin's lymphomas is highly suggestive of the involvement of a locally altered gene in this disease. In this study, we analyzed the potential involvement, in the translocation, of two receptor tyrosine kinase genes and putative oncogenes, FLT4 and FGFR4, previously localized near this breakpoint. Fluorescence in situ chromosomal hybridization allowed us to refine their localization to sub-band 5q35.3 and to show that both genes are translocated to the derivative chromosomes in Ki-1 cell lines containing either a t(2;5) or a t(3;5). Pulsed-field gel electrophoresis showed that the FLT4 and FGFR4 genes are not physically linked, nor are they altered by the translocation. Finally, Northern blot analysis showed that neither FLT4 nor FGFR4 is expressed in the Ki-1 cell lines, suggesting that they are not implicated in the genesis of Ki-1 lymphomas.
 ...
PMID:Localization of two tyrosine kinase receptor genes with respect to the 5q35 chromosomal breakpoint of Ki-1 lymphoma cell lines. 750 15

The tie gene encodes a receptor tyrosine kinase that together with its thus far unidentified ligand appears to play a distinct role in the regulatory pathway of early hematopoiesis and angiogenesis. Here, we attempted to define the possible involvement of tie in the pathobiology of hematopoietic malignancies by examining tie mRNA expression in human leukemia and lymphoma cells. We used a large panel of 93 well-characterized human continuous leukemia-lymphoma cell lines as model systems for the various hematopoietic cell lineages. At the Northern blot level, none of the 27 lymphoid leukemia or lymphoma-derived cell lines (originating from four B-precursor leukemia, four B-cell leukemia, four B-cell non-Hodgkin's lymphoma, two myeloma, two Burkitt lymphoma, four T-cell leukemia, five Hodgkin lymphoma, two anaplastic large cell lymphoma) tested expressed tie transcripts, whereas 23/42 (55%) of the myeloid cell lines analyzed expressed tie mRNA: in detail, 15 of 20 (75%) megakaryocytic, five of 11 (45%) erythroid, three of seven (43%) myelocytic and none of four monocytic cell lines were tie mRNA positive. In the reverse transcriptase-polymerase chain reaction analysis, which can detect very low levels of mRNA expression, all 12 myeloid cell lines and 19 of 39 (48%) lymphoid cell lines were positive. In experiments aimed at inducing cellular differentiation over an incubation period of 4 days, the phorbol ester PMA strongly enhanced tie mRNA expression in one erythroid and in one myelocytic cell line, but (like thrombopoietin) down-regulated tie mRNA expression in two megakaryocytic cell lines. Taken together these results indicate that tie is predominantly expressed in leukemia cells derived from the myeloid cell lineages (and here in particular in megakaryoblastic cells) and not in lymphoid leukemia cells. These observations provide some evidence for the hypothesis that tie is a receptor for a regulatory factor involved in normal and plausibly also leukemic hematopoiesis.
 ...
PMID:Expression of tie receptor tyrosine kinase in human leukemia cell lines. 930 79

The receptor tyrosine kinase Flt3 is expressed on the blasts of a high proportion of AML cases. We were interested in the expression and function of Flt3 on various human tumors. human tumor cell lines were tested for Flt3 expression by northern blot analysis and RT-PCR using head/neck (n=3), breast (n=4), ovarian (n=4), small cell lung (n=2), non-small cell lung (n=2), gastric (n=1), colon (n=3), pancreatic (n=1) and prostate carcinoma (n=1), choriocarcinoma (n=1), glioblastoma (n=5), neuroblastoma (n=1), melanoma (n=3), lymphoma (n=1), Hodgkin's disease (n=2), and leukemic (n=6) cell lines. With no expression on the other cell samples, 3 of 6 leukemic cell lines showed expression of Flt3 mRNA. The cDNA region corresponding to the juxtamembrane domain did not show any mutation as determined by sequence analysis. In all 3 positive cell lines, protein expression was verified by immunoprecipitation followed by immunoblot analysis. Although Flt3 is functional in these cell lines, as judged by ligand-dependent receptor autophosphorylation, it only mediates a proliferative response in 2 of the 3 cell lines. In conclusion, Flt3 is expressed exclusively in hematopoietic malignancies. Although early signalling events are detectable in all Flt3-positive cell lines tested, the expression of Flt3 does not predict a proliferative response of the cell lines. No internal tandem duplication of the juxtamembrane domain can be observed.
 ...
PMID:Expression and function of Flt3/flk2 in human tumor cell lines. 1008 27

The non-Hodgkin lymphoma (NHL) subtype anaplastic large-cell lymphoma (ALCL) is frequently associated with a t(2;5)(p23;q35) that results in the fusion of the ubiquitously expressed nucleophosmin (NPM) gene at 5q35 to the anaplastic lymphoma kinase (ALK) gene at 2p23, which is not normally expressed in hematopoietic tissues. Approximately 20% of ALCLs that express ALK do not contain the t(2;5), suggesting that other genetic abnormalities can result in aberrant ALK expression. Here we report the molecular characterization of an alternative genetic means of ALK activation, the inv(2)(p23q35). This recurrent abnormality produces a fusion of the amino-terminus of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), a bifunctional homodimeric enzyme that catalyzes the penultimate and final steps of de novo purine nucleotide biosynthesis, with the intracellular portion of the ALK receptor tyrosine kinase. RT-PCR analysis of 5 ALCL tumors that contained the inv(2) revealed identical ATIC-ALK fusion cDNA junctions in all of the cases. Transient expression studies show that the ATIC-ALK fusion transcript directs the synthesis of an approximately 87-kd chimeric protein that is localized to the cytoplasm, in contrast to NPM-ALK, which typically exhibits a cytoplasmic and nuclear subcellular distribution. ATIC-ALK was constitutively tyrosine phosphorylated and could convert the IL-3-dependent murine hematopoietic cell line BaF3 to cytokine-independent growth. Our studies demonstrate an alternative mechanism for ALK involvement in the genesis of NHL and suggest that ATIC-ALK activation results from ATIC-mediated homodimerization. In addition, expected decreases in ATIC enzymatic function in ATIC-ALK-containing lymphomas may render these tumors more sensitive to antifolate drugs such as methotrexate. (Blood. 2000;95:2144-2149)
 ...
PMID:Inv(2)(p23q35) in anaplastic large-cell lymphoma induces constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis. 1070 87

Despite its clinical and histological heterogeneity, anaplastic large cell lymphoma (ALCL) is now a well-recognized clinicopathological entity accounting for 2% of all adult non-Hodgkin's lymphomas (NHL) and about 13% of pediatric NHL. Immunophenotypically, ALCL are of T cell (predominantly) or Null cell type; by definition, cases expressing B cell antigens are officially not included in this entity. The translocation (2;5)(p23;q35) is a recurring abnormality in ALCL; 46% of the ALCL patients bear this signature translocation. This translocation creates a fusion gene composed of nucleophosmin (NPM) and a novel receptor tyrosine kinase gene, named anaplastic lymphoma kinase (ALK). The NPM-ALK chimeric gene encodes a constitutively activated tyrosine kinase that has been shown to be a potent oncogene. The exact pathogenetic mechanisms leading to lymphomagenesis remain elusive; however, the synopsis of evidence obtained to date provides an outline of likely scenarios. Several t(2;5) variants have been described; in some instances, the breakpoints have been cloned and the genes forming a new fusion gene with ALK have been identified: ATIC-ALK, TFG-ALK and TPM3-ALK. Cloning the translocation breakpoint and identifying the ALK and NPM genes provided tools for screening material from patients with ALCL using various approaches at the chromosome, DNA, RNA, or protein level: positive signals in the reverse transcriptase-polymerase chain reaction (RT-PCR) and the immunostaining with anti-ALK monoclonal antibodies (McAb) serve as the most convenient tests for detection of the t(2;5) NPM-ALK since the fusion gene and ALK protein expression do not occur in normal or reactive lymphoid tissue. The wide range of NPM-ALK positivity reported in different series appears to be dependent on the inclusion and selection criteria of the ALCL cases studied. Overall, however, 43% of ALCL cases were NPM-ALK+ (83% of pediatric ALCL vs 31% of adult ALCL). Occasional non-ALCL B cell lymphomas (4%) with diffuse large cell and immunoblastic histology and Hodgkin's disease cases (3%) were NPM-ALK-, but these data are questionable. The aggregate results indicate that, in contrast to primary nodal (systemic) ALCL, the t(2;5) may be present in only 10-20% of primary cutaneous ALCL and rarely, if at all, in lymphomatoid papulosis, a potential precursor lesion; however, these 10-20% positive cases were not confirmed by anti-ALK McAb immunostaining and may represent an overestimate. Positivity for NPM-ALK is associated to various degrees with the following parameters: 44% and 45% of ALCL cases with T cell and Null cell immunophenotype, respectively, are positive, whereas only 8% of cases with a B cell immunoprofile are positive; the mean age of positive patients is significantly younger than that of negative patients; positive cases carry a better overall prognosis (but not in all studies). Recently, the homogenous category of ALK lymphoma ('ALKoma') has emerged as a distinct pathological entity within the heterogenous group of ALCL. The fact that patients with ALK lymphomas experience significantly better overall survival than ALK- ALCL demonstrates further that analysis of ALK expression has important prognostic implications. The term ALK lymphoma signifies a switch in the use of the diagnostic criteria: cases are selected on the basis of a genetic abnormality (the ALK rearrangement), instead of the review of morphological or immunophenotypical features which are clearly more prone to disagreement and controversy. Since its initial description in 1985 ALCL has become one of the best characterized lymphoma entities.
 ...
PMID:Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas. 1099 99

Angiogenesis is an important component in the progression and metastasis of solid tumors. We now appreciate that angiogenesis is also critically involved in the pathogenesis of hematologic malignancies. Current data suggest important prognostic and therapeutic implications of angiogenesis in a variety of malignancies of the hematopoietic system, including acute and chronic leukemias, myeloproliferative diseases, multiple myeloma, non-Hodgkin's lymphomas, and Hodgkin's disease. Vascular endothelial growth factor (VEGF) is a major angiogenic factor that regulates multiple endothelial cell functions, including mitogenesis. Cellular and circulating levels of VEGF are elevated in hematologic malignancies and are adversely associated with prognosis. Angiogenesis is a very complex, tightly regulated, multistep process, the targeting of which may well prove useful in the creation of novel therapeutic agents. Current approaches being investigated include the inhibition of angiogenesis stimulants (e.g., VEGF), or their receptors, blockade of endothelial cell activation, inhibition of matrix metalloproteinases, and inhibition of tumor vasculature. Preclinical, phase I, and phase II studies of both monoclonal antibodies to VEGF and blockers of the VEGF receptor tyrosine kinase pathway indicate that these agents are safe and offer potential clinical utility in patients with hematologic malignancies.
 ...
PMID:The vascular endothelial growth factor (VEGF) signaling pathway: a therapeutic target in patients with hematologic malignancies. 1170 Mar 90

Classic Hodgkin's disease (cHD) is a lymphoid neoplasia characterized by few malignant Hodgkin and Reed-Sternberg (H-RS) cells, embedded in an abundant background of non-tumour cells. We have previously demonstrated the expression in primary H-RS cells of the receptor tyrosine kinase (RTK) c-kit; here we describe its functional role in the cross-talk between H-RS cells themselves with neighbouring cell populations. In particular, we analysed the expression of c-kit and its ligand stem cell factor (SCF) in a panel of HD-derived cell lines and fibroblasts from HD-involved lymph nodes (HDF). While c-kit was expressed by HD-derived cell lines, usually in the absence of SCF, this latter molecule, in its soluble and/or membrane-bound (mb) form, was in turn expressed at a high level by primary HDF. In vitro adhesion between HD-derived cell lines and HDF was mainly mediated by c-kit/SCF interactions, and this phenomenon was significantly inhibited by an excess of soluble SCF or by neutralizing anti-c-kit monoclonal antibodies. Furthermore, both soluble and mb-SCF increased growth and colony survival of HD-derived cell lines; these effects were significantly enhanced upon co-stimulation of H-RS cells with interleukin 9. Finally, soluble SCF was able to partially rescue H-RS cells from apoptosis induced by serum starvation. Taken together, our data indicated the expression of functional c-kit receptor by H-RS cells and suggests a role of SCF in the pathobiology of cHD.
 ...
PMID:Hodgkin and Reed-Sternberg cells express functional c-kit receptors and interact with primary fibroblasts from Hodgkin's disease-involved lymph nodes through soluble and membrane-bound stem cell factor. 1219 85

Stimulation of CD28 alone has been shown to regulate cytokine gene transcription and expression of the type 1 insulin-like growth factor receptor (IGF-1R) in lymphocytes. In this study, the ephrin receptor tyrosine kinase ephA3, was identified as a new CD28-responsive gene in Jurkat cells by using a human cytokine/receptor array. EphA3 was not detected in normal peripheral T cells, in any subset of thymus-derived developing T cells, or in Hodgkin's lymphoma. However, contrary to previous findings, EphA3 was detected in a panel of T-cell lymphomas. Stimulation of Jurkat cells with ephrin-A5 resulted in loss of cell adhesion to fibronectin and recruitment of the adapter protein CrkII to EphA3. Interestingly, EphA3 expression in CD28-stimulated Jurkat cells was enhanced by IGF-1 or by overexpression of the IGF-1R, and was suppressed by anti-IGF-1R blocking antibodies. The data suggest that CD28- and IGF-1-regulated expression of EphA3 is associated with adherence and that it may be involved in the motility of malignant T cells.
 ...
PMID:EphA3 is induced by CD28 and IGF-1 and regulates cell adhesion. 1469 37

Angiogenesis is defined as the formation of new capillaries from prexisting blood vessels and plays an important role in the progression of solid tumors and hematologic malignancies. Markers of angiogenesis correlate with clinical characteristics in leukemia and non-Hodgkin's-lymphoma, serving as predictors of poor prognosis. Antiangiogenic effects of chemotherapeutics as well as of novel drugs such as farnesyltransferase inhibitors and tyrosine kinase inhibitors such as Gleevec might contribute to their therapeutic potential. Thalidomide which has antiangiogenic effects and direct cytotoxic effects was found to be effective in multiple myeloma and is considered as an established treatment modality for patients with refractory or relapsed multiple myeloma. Thalidomide has a significant therapeutic effect in myelodysplastic syndrome (MDS) by improving cytopenia and achieving independence of transfusion therapy in a subset of patients. Preliminary data indicate activity of specific VEGF receptor tyrosine kinase (RTK) inhibitors in multiple myeloma (MM) and acute myeloid leukemia (AML). The positive correlation between increased levels of angiogenic cytokines and clinical response to VEGF-RTK inhibitors and thalidomide indicates the relevance of detecting angiogenesis markers to identify best candidate patients for specific approaches. Including antiangiogenic drugs into treatment protocols for hematologic malignancies is an important task for future clinical studies.
 ...
PMID:Antiangiogenic therapy in hematologic malignancies. 1507 37

The pathogenesis of Hodgkin lymphoma (HL) is still largely unknown. Based on a search for footprints of pathogenetic mechanisms in global RNA expression data of Hodgkin/Reed-Sternberg (HRS) cell lines, we analyzed the expression and activation of 6 receptor tyrosine kinases (RTKs) in classic HL. Immunohistochemistry revealed that the RTKs platelet-derived growth factor receptor A (PDGFRA), DDR2, EPHB1, RON, TRKB, and TRKA were each expressed in HRS cells in 30% to 75% of patients. These RTKs were not expressed in normal B cells, the origin of HRS cells, or in most B-cell non-Hodgkin lymphoma (NHL). In the majority of patients at least one RTK was expressed, and in most patients several RTKs were coexpressed, most prominently in Hodgkin lymphoma of the nodular sclerosis subtype. Phosphotyrosine-specific antibodies revealed exemplarily the activation of PDGFRA and TRKA/B and an elevation of cellular phosphotyrosine content. Immunohistochemistry for RTK ligands indicated that DDR2 and TRKA are likely activated in a paracrine fashion, whereas PDGFRA and EPHB1 seem to be activated by autocrine loops. Activating mutations were not detected in cDNA encoding the RTKs in HRS cell lines. These findings show the unprecedented coexpression of multiple RTKs in a tumor and indicate that aberrant RTK signaling is an important factor in HL pathogenesis and that it may be a novel therapeutic target.
 ...
PMID:Autocrine- and paracrine-activated receptor tyrosine kinases in classic Hodgkin lymphoma. 1567 64


1 2 3 Next >>