UNIPROT:Q06643 - FACTA Search

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Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anaplastic large cell lymphoma (ALCL) is a subtype of non-Hodgkin's lymphoma characterized by the CD30+ large neoplastic cells and sometimes carries a t(2;5)(p23;q35). Recently, we found a novel hyperphosphorylated 80-kD protein tyrosine kinase, p80, in ALCLs with t(2;5). Subsequent cDNA cloning showed p80 to be a fusion protein of two genes, the novel tyrosine kinase gene and the nucleophosmin gene, in accordance with the sequence of the NPM/ALK gene (Morris et al, Science 263:1281, 1994). Meanwhile, the clinicopathologic features of p80-carrying ALCLs have remained unclear. Paraffin sections of 105 cases of ALCL were immunostained using anti-p80 antibody, and 30 of them were shown to express p80. Clinicopathologic comparison between p80-positive and -negative ALCLs showed that p80-positive cases occurred in a far younger patient age group (16.2 +/- 12.9 years; p80-negative cases, 51.0 +/- 22.3 years; P < .0001) and the patients showed a far better 5-year survival rate (79.8%; p80-negative group, 32.9%; P < .01). These data showed that p80-positive ALCL is a distinct entity both clinically and pathogenetically and should be differentiated from p80-negative ALCL.
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PMID:Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK: a distinct clinicopathologic entity. 765 22

The classification of malignant lymphoma has been based on morphological and immunophenotypical findings for a long time. Recently, as chromosomal and genomic abnormalities which closely relate to the specific subtypes of lymphoma are revealed, these factors becoming much more important in the evaluation of differences in clinicopathological features of the various lymphoma subtypes. Anaplastic large cell lymphoma (ALCL) is a subtype of non-Hodgkin's lymphoma (NHL) involving large CD30+ neoplastic cells, which occasionally carries the chromosomal translocation t(2;5)(p23;q35). We have recently found a novel hyperphosphorylated 80-kDa protein tyrosine kinase, p80 which is expressed specifically in human ALCLs with this translocation. Subsequent cDNA cloning showed p80 to be a fusion protein of two genes, the novel tyrosine kinase gene and the nucleophosmin gene, in accordance with the sequence of the NPM/ALK gene. In order to clarify the clinicopathologic features of p80-carrying ALCLs, we developed an anti-p80 polyclonal antibody, which immunoprecipitated, immunoblotted and immunostained p80 specifically. When paraffin sections of 105 cases of ALCL were stained using the anti-p80 antibody, 30 were shown to be p80 positive Clinicopathological comparison between p80-positive and p80-negative ALCLs revealed that the p80-positive cases occurred in a much younger patient age group and that the patients showed a far better 5-year survival rate. These data suggest that p80-positive ALCL is a distinct entity and should be differentiated from p80-negative ALCL.
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PMID:The clinicopathological features of anaplastic large cell lymphomas expressing p80NPM/ALK. 902 82

Hepatocyte growth factor (HGF)/scatter factor (SF) is the ligand for a tyrosine kinase cell surface receptor encoded by the MET protooncogene (c-MET). HGF/SF can induce proliferation and motility in epithelial cells and promotes invasion of carcinoma cells and NIH3T3 fibroblasts transfected with both HGF/SF and c-MET genes. Our results show that HGF/ SF and c-MET also play a role in adhesion and invasion of human lymphoma cells. c-MET mRNA is expressed in hemopoietic cells, such as hemopoietic progenitor cells (CD34+ cells) in bone marrow (BM) and mobilized peripheral blood, immature B cells in cord blood and BM, and germinal center B-centroblasts. In normal peripheral blood B cells, which are c-MET-, c-MET expression was induced by PMA, ConA, HGF/ SF, and Epstein-Barr virus (EBV) infection. Using immunohistochemistry, we detected c-MET on the cell surface of large activated centroblasts in lymph nodes from patients with B-non-Hodgkin's lymphoma and Hodgkin's disease. In the latter group, c-MET expression correlated well with the presence of EBV. Because HGF/SF and c-MET promote metastasis of carcinoma cells, we studied the effects of c-MET stimulation by HGF/SF of B-lymphoma cells on properties relevant for metastasis, ie, adhesion, migration, and invasion. HGF/SF stimulated adhesion of the c-MET+ B-cell lines to the extracellular matrix molecules fibronectin (FN) and collagen (CN) in a dose dependent manner. However, adhesion to laminin was not affected by HGF/SF. Adhesion to FN was mediated by beta 1-integrins alpha 4 beta 1 (VLA4) and alpha 5 beta 1 (VLA5) since blocking antibodies against beta 1- (CD29), alpha 4-(CD49d), or alpha 5- (CD49e) integrin subunits, completely reversed the effect of HGF/SF. Furthermore, HGF/SF induced adhesion was abrogated by addition of genistein, which blocks protein tyrosine kinases, including c-MET. Addition of HGF/SF resulted in a sixfold increase in migration of c-MET B-lymphoma cells through Matrigel, compared to medium alone. In rat fibroblast cultures, HGF/SF doubled the number of c-MET+ B-lymphoma cells that invaded the fibroblast monolayer. In these adhesion, migration and invasion assays HGF/SF had no effect on c-MET- cell lines. In conclusion, c-MET is expressed or can be induced on immature, activated, and certain malignant B cells. HGF/SF increased adhesion of c-MET+ B-lymphoma cells to FN and CN, mediated via beta 1-integrins alpha 4 beta 1 and alpha 5 beta 1, and furthermore promoted migration and invasion.
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PMID:Hepatocyte growth factor/scatter factor promotes adhesion of lymphoma cells to extracellular matrix molecules via alpha 4 beta 1 and alpha 5 beta 1 integrins. 902 31

Anaplastic Lymphoma Kinase (ALK) was originally identified as a member of the insulin receptor subfamily of receptor tyrosine kinases that acquires transforming capability when truncated and fused to nucleophosmin (NPM) in the t(2;5) chromosomal rearrangement associated with non-Hodgkin's lymphoma, but further insights into its normal structure and function are lacking. Here, we characterize a full-length normal human ALK cDNA and its product, and determine the pattern of expression of its murine homologue in embryonic and adult tissues as a first step toward the functional assessment of the receptor. Analysis of the 6226 bp ALK cDNA identified an open reading frame encoding a 1620-amino acid (aa) protein of predicted mass approximately 177 kDa that is most closely related to leukocyte tyrosine kinase (LTK), the two exhibiting 57% aa identity and 71% similarity over their region of overlap. Biochemical analysis demonstrated that the approximately 177 kDa ALK polypeptide core undergoes co-translational N-linked glycosylation, emerging in its mature form as a 200 kDa single chain receptor. Surface labeling studies indicated that the 200 kDa glycoprotein is exposed at the cell membrane, consistent with the prediction that ALK serves as the receptor for an unidentified ligand(s). In situ hybridization studies revealed Alk expression beginning on embryonic day 11 and persisting into the neonatal and adult periods of development. Alk transcripts were confined to the nervous system and included several thalamic and hypothalamic nuclei; the trigeminal, facial, and acoustic cranial ganglia; the anterior horns of the spinal cord in the region of the developing motor neurons; the sympathetic chain; and the ganglion cells of the gut. Thus, ALK is a novel orphan receptor tyrosine kinase that appears to play an important role in the normal development and function of the nervous system.
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PMID:ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK) 917 53

In this study, we examined a large number of patients to clarify the distribution and frequency of a recently described FLT3 tandem duplication among hematopoietic malignancies, including 112 acute myelocytic leukemia (AML), 55 acute lymphoblastic leukemia (ALL), 37 myelodysplastic syndrome (MDS), 20 chronic myelogenous leukemia (CML), 30 non-Hodgkin's lymphoma (NHL), 14 adult T cell leukemia, 15 chronic lymphocytic leukemia (CLL) and 38 multiple myeloma (MM). We also evaluated 71 cell lines derived from 11 AML, 31 ALL, two hairy cell leukemia, three acute unclassified leukemia, 10 CML, 12 NHL including six Burkitt's lymphoma, and two MM. Using genomic PCR of exon 11 coding for the juxtamembrane (JM) domain and first amino acids of the 5'-tyrosine kinase (TK) domain, this length mutation was found only in AML (22/112, 20%) and MDS (1/37). According to the FAB subclassification, they were 5/18 (28%) of M1, 4/29 (14%) of M2, 3/17 (18%) of M3, 6/24 (25%) of M4, 4/20 (20%) of M5 and 1/9 of refractory anemia with excess of blast in transformation. In the various cell lines examined, this abnormality was determined in only one derived from AML and never found in other hematological malignancies. The sequence analysis of the abnormal PCR products revealed that 23 of 24 showed internal tandem duplication with or without insertion of nucleotides. In one AML, insertion and deletion without duplication was determined. All 24 lengthened sequences were in-frame. Duplication takes place in the sequence coding for the JM domain and leaves the TK domain intact. In conclusion, we emphasize that the length mutation of FLT3 at JM/TK-I domains were restricted to AML and MDS. Since all these mutations resulted in in-frame, this abnormality might function for the proliferation of leukemic cells.
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PMID:Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines. 932 77

A recently described atypical myeloproliferative disorder is invariably associated with reciprocal translocations involving 8p11-12. The most common rearrangement is a t(8;13)(p11;q11-12). Here we determine that this translocation results in the fusion of the fibroblast growth factor receptor 1 gene (FGFR1), a member of the receptor tyrosine kinase family at 8p11, to a novel gene at 13q11-12 designated RAMP . The predicted RAMP protein exhibits strong homology to the product of a recently cloned candidate gene for X-linked mental retardation, DXS6673E . We also provide the first report of a novel, putative metal-binding motif, present as five tandem repeats in both RAMP and DXS6673E. RT-PCR detected only one of the two possible fusion transcripts, encoding a product in which the N-terminal 641 amino acids of RAMP become joined to the tyrosine kinase domain of FGFR1. Receptor tyrosine kinases are not commonly involved in the formation of tumour-specific fusion proteins. However, the previous reports of involvement of receptor tyrosine kinases in fusion proteins in non-Hodgkin's lymphoma, chronic myelomonocytic leukaemia and papillary thyroid carcinoma described similar rearrangements. By analogy with these, we propose that the RAMP-FGFR1 fusion product will contribute to progression of this myeloproliferative disorder by constitutive activation of tyrosine kinase function.
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PMID:The t(8;13)(p11;q11-12) rearrangement associated with an atypical myeloproliferative disorder fuses the fibroblast growth factor receptor 1 gene to a novel gene RAMP. 949 16

A recurrent, reciprocal balanced translocation, t(2;5) (p23;q35), has been recognized in CD30+ anaplastic large-cell lymphomas (ALCL), a newly recognized subtype comprising approximately 5% of all non-Hodgkin's lymphoma (NHL). This translocation creates a novel fusion protein, NPM-ALK, which has transforming properties in vitro and can cause large-cell lymphoma in vivo when transfected into murine bone marrow. Multiple techniques including reverse transcriptase-polymerase chain reaction (RT-PCR) amplification of NPM-ALK fusion transcripts, genomic DNA-PCR, RNA in situ hybridization, and fluorescence in situ hybridization (FISH) of metaphase chromosomes and interphase nuclei, and immunohistochemical detection of the 80 kilodalton protein (p80) derived from the NPM-ALK fusion have enabled surveys of normal and lymphoma tissues for evidence of the translocation. These studies suggest that expression of ALK protein, a novel orphan receptor tyrosine kinase, is normally confined to the nervous system. In lymphoma, NPM-ALK expression is most often seen in young patients with the monomorphic or small-cell variant of ALCL who present with advanced stage disease and have tumors with a CD30+, T- or null-cell phenotype. It is less frequently detected in older patients and in ALCL of pleomorphic histology. In addition, expression of NPM-ALK has been found in occasional CD30 negative B-cell lymphomas with diffuse large cell or immunoblastic histology. NPM-ALK is rarely, if ever, detected in Hodgkin's disease or secondary ALCL. Although initially found in primary nodal ALCL, recent studies suggest that NPM-ALK expression may occur in lymphoma at extranodal sites, including the skin; it remains controversial, however, whether CD30+ primary cutaneous lymphoma and its benign counterpart, lymphomatoid papulosis (LyP), express NPM-ALK in some cases. A retrospective study has suggested that expression of NPM-ALK is associated with a better overall 5-year survival; these results must be confirmed in prospective studies of patients with uniform staging and therapy to more fully understand the clinical significance of the t(2;5) and its novel chimeric protein, NPM-ALK.
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PMID:The t(2;5) in human lymphomas. 968 23

Large-cell anaplastic lymphoma is a subtype of non-Hodgkin's lymphoma characterized by the expression of CD30. More than half of these lymphomas have a chromosomal translocation, t(2;5), that leads to the expression of a hybrid protein comprised of the nucleolar phosphoprotein nucleophosmin (NPM) and the anaplastic lymphoma kinase (ALK). Here we show that transfection of the constitutively active tyrosine kinase NPM-ALK into Ba/F3 and Rat-1 cells leads to a transformed phenotype. Oncogenic tyrosine kinases transform cells by activating the mitogenic signal transduction pathways, e.g., by binding and activating SH2-containing signaling molecules. We found that NPM-ALK binds most specifically to the SH2 domains of phospholipase C-gamma (PLC-gamma) in vitro. Furthermore, we showed complex formation of NPM-ALK and PLC-gamma in vivo by coimmunoprecipitation experiments in large-cell anaplastic lymphoma cells. This complex formation leads to the tyrosine phosphorylation and activation of PLC-gamma, which can be corroborated by enhanced production of inositol phosphates (IPs) in NPM-ALK-expressing cells. By phosphopeptide competition experiments, we were able to identify the tyrosine residue on NPM-ALK responsible for interaction with PLC-gamma as Y664. Using site-directed mutagenesis, we constructed a comprehensive panel of tyrosine-to-phenylalanine NPM-ALK mutants, including NPM-ALK(Y664F). NPM-ALK(Y664F), when transfected into Ba/F3 cells, no longer forms complexes with PLC-gamma or leads to PLC-gamma phosphorylation and activation, as confirmed by low IP levels in these cells. Most interestingly, Ba/F3 and Rat-1 cells expressing NPM-ALK(Y664F) also show a biological phenotype in that they are not stably transformed. Overexpression of PLC-gamma can partially rescue the proliferative response of Ba/F3 cells to the NPM-ALK(Y664F) mutant. Thus, PLC-gamma is an important downstream target of NPM-ALK that contributes to its mitogenic activity and is likely to be important in the molecular pathogenesis of large-cell anaplastic lymphomas.
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PMID:Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity. 981 83

The authors examined the pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in 17 patients (4 children, 13 adults) with B-lineage lymphoid malignancies, including 12 patients with acute lymphoblastic leukemia (ALL) and 5 patients with non-Hodgkin's lymphoma (NHL). The immunoconjugate was administered intravenously as a 1-hour continuous infusion at a dose level of either 0.1 mg/kg (N = 12) or 0.18 mg/kg (N = 5), and the plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameters. Pharmacokinetic analyses revealed a plasma half-life of 19 +/- 4 hours, mean residence time of 22 +/- 4 hours, and a systemic clearance of 18 +/- 2 mL/h/kg. The average (mean +/- SEM) values for the maximum plasma concentration Cmax, volume of distribution at steady state (Vss), and area under curve (AUC) were 1092 +/- 225 ng/ml, 291 +/- 37 mL/kg, and 9987 +/- 2021 micrograms x h/L, respectively. The AUC values were higher at the 0.18 mg/kg dose level than at the 0.1 mg/kg dose level (16,848 +/- 5118 micrograms x h/L vs. 7128 +/- 1156 micrograms x h/L, p = 0.009). Patients with ALL had a significantly larger volume of distribution at steady state (332 +/- 47 mL/kg vs. 191 +/- 12 mL/kg, p = 0.04), faster clearance (21 +/- 3 mL/h/kg vs. 11 +/- 2 mL/h/kg, p = 0.03), and lower dose-corrected AUC than patients with NHL (6010 +/- 836 micrograms x h/L vs. 12,044 +/- 2707 micrograms x h/L, p = 0.006). There was a trend toward faster clearance rates (23 +/- 4 mL/h/kg vs. 16 +/- 3 mL/h/kg, p = 0.1), shorter elimination half-lives (5.7 +/- 3.6 hours vs. 13 +/- 8.8 hours, p = 0.1), and shorter mean residence times (11 +/- 3 hours vs. 25 +/- 5 hours, p = 0.08) for non-Caucasian patients as compared to Caucasian patients. When compared to adult patients, pediatric patients showed a significantly larger volume of distribution at steady state (418 +/- 82 mL/kg vs. 252 +/- 34 mL/kg, p = 0.02) and a longer elimination half-lives (18.4 +/- 13.6 hours vs. 8.7 +/- 6.7 hours, p = 0.04). The pharmacokinetics of B43-Genistein was not affected by the gender of the patients or by bone marrow transplantation in past medical history. Overall, B43-Genistein showed favorable pharmacokinetics in this heavily pretreated leukemia/lymphoma patient population, which is reminiscent of its recently reported favorable pharmacokinetics in cynomolgus monkeys. To our knowledge, this is the first clinical pharmacokinetics study of a tyrosine kinase inhibitor containing immunoconjugate.
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PMID:Clinical pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in patients with B-lineage lymphoid malignancies. 1058 90

ASCO 2000 did not offer revolutionary new advances in the treatment of hematologic malignancies. However, reports at the meeting built incrementally on gains established over the past several years. The meeting continued to highlight advances in the targeted therapy of hematologic malignancies. Excitement abounds regarding the clinical development of STI 571, a rationally designed tyrosine kinase inhibitor, for the treatment of chronic myelogenous leukemia. Studies further defined the role monoclonal antibody treatment for non-Hodgkin's lymphoma and more mature data were presented on both unconjugated antibody therapy and radioimmunoconjugates. In disease detection, important data were presented to clarify the role of positron emission tomography scans in the staging and follow-up of lymphoid malignancies. The following review summarizes key abstracts presented at the 2000 ASCO meeting and will elaborate on the implications of these findings for disease management.
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PMID:Hematologic malignancies: selected abstracts and commentary. 1096 94

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