Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ifosfamide/mesna was given to 97 patients who had malignant solid tumors diagnosed before they were 21 years of age. Patients received 1.6 g/m2 ifosfamide daily x 5, given i.v. over 15 min, followed by 400 mg/m2 i.v. mesna at 15 min and 4 and 6 h after ifosfamide. Responses were noted in patients with osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma and other soft-tissue sarcomas, rhabdoid tumor, neuroblastoma, Wilms' tumor, primitive neuroectodermal tumor, retinoblastoma, germ-cell tumors, and B-cell lymphoma. Toxicity included mild to moderate nausea and vomiting, transient, reversible myelosuppression, transient elevations of serum blood urea nitrogen (BUN) and creatinine and liver enzymes, infections, and self-limiting neurotoxicity characterized by changes in mental status, motor dysfunction, cranial nerve palsy, cerebellar dysfunction, and seizures. Neurotoxic symptoms were generally seen in patients who had previously received cisplatin. Ifosfamide is an important alkylating agent that should be combined with other agents in phase II and III trials. Alternate dose schedules should also be investigated.
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PMID:Ifosfamide in pediatric malignant solid tumors. 250 57

Ifosfamide was given to 61 patients with malignant solid tumors diagnosed before the age of 21 years. In this phase II study, all patients received 1.6 g/m2/day X 5 iv over 15 minutes followed by mesna at a dose of 400 mg/m2 iv at 15 minutes and 4 and 6 hours after ifosfamide. Responses were observed in five of 15 patients with osteosarcoma, two of ten with neuroblastoma, two of six with Wilms' tumor, two of five with rhabdomyosarcoma, four of eight with other soft tissue sarcomas, one of one with retinoblastoma, one of two with germ cell tumors, one of one with B-cell lymphoma, and one of one with a primitive neuroectodermal tumor. Fifty-nine of 61 patients had received prior alkylating agent therapy which included cyclophosphamide, cisplatin, mechlorethamine, melphalan, or dacarbazine. Fourteen of 19 responses developed in patients whose tumors were resistant to treatment with cyclophosphamide. A patient with malignant Schwannoma who had received no prior chemotherapy developed a complete response which lasted 12 months. A patient with brain metastases of osteosarcoma has had complete response for greater than 2 years. Complete response was also observed in a patient with B-cell lymphoma. Toxicity consisted of mild to moderate nausea and vomiting, transient reversible myelosuppression, occasional elevation of serum BUN or creatinine, and transient neurotoxicity characterized by somnolence, confusion, weakness, tremor, hallucinations, or seizures. We conclude that ifosfamide is an important alkylating agent without apparent complete cross-resistance with cyclophosphamide, and as such should be further investigated for determination of its activity in patients with pediatric neoplasms and considered for incorporation into phase II-III trials for certain tumors.
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PMID:Phase II trial of ifosfamide in children with malignant solid tumors. 310 34

Mutations of p53 have been suggested to be involved in the histologic transformation of follicular lymphoma, but the role of the retinoblastoma (RB) gene, another tumor suppressor gene, in lymphomagenesis has not been established. To determine the roles of these tumor suppressor genes and their relationship with the anti-apoptotic bcl-2 gene in follicle center lymphoma, the immunohistochemical expression of p53, bcl-2, and RB proteins was correlated with cytologic grade in 50 cases of follicular lymphoma, and the results were compared to 23 cases of diffuse large B-cell lymphoma. The results showed that only 2 of 25 grade 1 follicular lymphoma were p53-positive compared to 16 of 25 grade 3 cases (P <.0001). A significantly lower number (13 of 25) of grade 3 follicular lymphomas expressed bcl-2 compared to grade 1 cases (23 of 25) (P <.004). Eight of 14 bcl-2-negative follicular lymphomas expressed p53, compared with 10 of 36 bcl-2-positive cases (P = .1). Twenty-four of 25 grade 3 follicular lymphomas showed 2+ to 3+ staining for RB protein compared to 9 of 21 grade 1 cases (P <.0002). Expression of p53 protein correlates significantly with higher cytologic grade in follicular lymphoma. Similar to earlier studies of breast cancer and lymphoma, there appears to be an inverse relationship between p53 and bcl-2 expression in follicular lymphoma. Inactivation of the retinoblastoma gene does not seem to be involved in the histogenesis of follicle center lymphoma or diffuse large B-cell lymphoma.
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PMID:Immunohistochemical detection of p53, bcl-2, and retinoblastoma proteins in follicular lymphoma. 862 59

The product of the retinoblastoma tumor-suppressor gene (pRB), a nuclear phosphoprotein that regulates transcription factors such as E2F, is involved in cell cycle control and differentiation. Its activity is regulated by phosphorylation; the underphosphorylated form inhibits transcription whereas the highly phosphorylated form is inactive. Cyclin D1 and its associated kinase (CDK 4/6) phosphorylate pRB in vitro, and therefore are thought to contribute to the regulation of pRB function. To examine the effect of cyclin D1 overexpression on pRB in primary tumor tissue, we studied pRB expression in low-grade B-cell neoplasms, with particular regard to mantle cell lymphoma, which is characterized by cyclin D1 (bcl-1) overexpression. pRB expression was studied by immunostaining with a well-characterized anti-pRB antibody; the phosphorylation status of pRB was examined by immunoblots; and the functional binding capacity of pRB was examined by in vitro binding to adenovirus E1A protein. We studied 3 reactive lymph nodes, 28 low grade B-cell lymphomas, 4 cases of hairy cell leukemia (HCL) and 3 plasmacytomas. Reactive lymph nodes showed intense pRB staining of germinal centers, with strongest (2+) staining in the large cells (centroblasts) of the proliferating (dark) zone and weak or no staining of small lymphocytes, including those of the mantle zone. In B-chronic lymphocytic leukemia (B-CLL) (4 cases), follicular lymphoma (3 cases) and mucosa-associated (MALT) lymphoma (3 cases) strong (2+) pRB staining was limited to centroblasts in reactive and neoplastic follicles and occasional proliferation centers, with only faint staining of small lymphoid cells. In contrast, 15 of 16 cases of mantle cell lymphoma showed strong (1-2+) staining of most cells; one blastoid mantle cell lymphoma showed only faint pRB staining. All cases of (HCL) and plasmacytoma showed strong pRB staining. Although most lymphomas with strong pRB expression were cyclin D1(+), three cyclin D1(+) cases showed only weak pRB expression (1 B-CLL, 1 blastoid mantle cell, 1 unclassifiable low grade B-cell lymphoma). Conversely, of the 4 pRB(+) HCLs and 3 pRB(+) plasmacytomas, only 1 of each was cyclin D1(+). pRB appeared to exist primarily in the underphosphorylated (fastest migrating) form on Western blot, despite the fact that cyclin D1 was complexed to CDK4, a form in which it normally phosphorylates pRB. In addition, pRB appeared to be unmutated, because it bound normally to the adenovirus E1A protein and showed nuclear localization by immunostaining. We conclude that most cases of mantle cell lymphoma, HCL, and plasmacytoma show high levels of pRB in contrast to follicle center lymphoma and small lymphocytic lymphoma; however, pRB expression does not appear to be consistently related to cyclin D1 overexpression. The pRB appears to be unmutated and underphosphorylated, and therefore should be in its active form. Our data from primary lymphoma tissue suggests that overexpression of cyclin D1, whereas tumorigenic, does not lead to pRB loss or hyperphosporylation. Thus, the mechanism by which cyclin D1 contributes to tumorigenesis and the significance of the restricted expression of pRB in low-grade lymphoid neoplasms remain to be determined.
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PMID:Expression of the retinoblastoma protein in low-grade B-cell lymphoma: relationship to cyclin D1. 870 83

Cross-linking surface immunoglobulin (Ig)M on the WEHI-231 B-cell lymphoma results in decreased cell size, G1/S growth arrest, and finally DNA cleavage into oligonucleosomal fragments that are the classical features of apoptotic cells. Treatment of WEHI-231 cells with anti-IgM in early G1 phase prevents phosphorylation of the retinoblastoma gene product (pRb) and inhibits entry into S phase. Using unsynchronized cells, we previously demonstrated that cyclin A-associated and Cdk2-dependent GST-pRb kinase activity were inhibited in WEHI-231 cells treated with anti-IgM. We now show that progression of elutriated early G1 phase WEHI-231 cells from early into late G1 phase is accompanied by an increase in the abundance of cyclin A protein and cyclin A-associated kinase activity. Treatment of early G1 cells with anti-IgM prevented this increase in cyclin A-associated kinase activity at late G1, despite minimal changes in the overall level of cyclin A and Cdk2 proteins. Late G1 cells, which already possess high cyclin A-associated kinase activity, were insensitive to anti-IgM treatment and were able to complete the cell cycle. We also found that anti-IgM-treated cells contained increased amounts of the Cdk inhibitor protein p27Kip1. Essentially all of the cyclin A in treated cells was associated with p27, a result which we propose explains the lack of cyclin A/Cdk2 kinase activity. Accumulation of p27 in cyclin A kinase complexes, however, did not decrease the amount of Cdk2 bound to cyclin A. Thus, cross-linking IgM on growth-inhibitable B-cell lymphomas affects cyclin A kinase activity by increasing the levels of p27 in this complex, thus preventing productive pRb phosphorylation and leading to cell cycle arrest and subsequent apoptosis. These results are discussed in terms of the cell cycle restriction points that regulate lymphocyte function, as well as the lineage-specific differences in cell cycle control.
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PMID:Role of cyclin A and p27 in anti-IgM induced G1 growth arrest of murine B-cell lymphomas. 873 99

Genetic alterations in the p107 gene, a close relative of the retinoblastoma tumor suppressor gene, have never been identified in human malignancies. When we searched for such alterations in human hematologic malignancies by Southern blot analysis, 2 of 21 cell lines and 1 of 88 primary disorders had genomic alterations within the gene. Particularly, an altered p107 gene in a diffuse-large B-cell lymphoma cell line, KAL-1, harbored an intragenic deletion of about 15 kbp leading to the expression of an altered p107 mRNA devoid of 819 nucleotides of the coding sequences, which predicts to encode an approximately 87-kDa protein. This cell line was found to express solely a p107 derivative of 84 kDa by immunoblotting analysis. These results suggest that alterations in the p107 gene are probably related to a limited subset of human hematologic malignancies.
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PMID:Genetic alterations in the retinoblastoma protein-related p107 gene in human hematologic malignancies. 979 Sep 44

The B cell lymphoma WEHI-231 has been used as a model to study immature B cell tolerance, based on its capacity to undergo growth arrest and programmed cell death on B cell receptor (BCR) cross-linking. Using this model to identify the molecular mechanisms underlying these processes, we found that BCR cross-linking results in the selective activation of caspase 7/Mch3, but not of the other two members of the CPP32 family, caspase 2/Nedd2 and caspase 3/CPP32. This was evidenced by the induction of proteolytic activity against the substrate for the CPP32 subfamily of caspases (z-DVED-AMC) in vitro, as well as PARP proteolysis in vivo and by the processing of the 35 kDa Mch3 into a 32 kDa species, which was later further proteolyzed. The general caspase inhibitor z-VAD-fmk, but not the CPP32 family inhibitor Ac-DEVD-CHO, blocked anti- micro-induced apoptosis, indicating that a caspase not belonging to the CPP32-like family is also implicated in anti- micro-triggered apoptosis. In contrast, z-VAD-fmk was not able to counteract growth arrest induced by anti- micro treatment, suggesting that caspase activation is not necessary for induction of growth arrest. Neither of the inhibitors prevented Mch3 processing; however, z-VAD-fmk prevented proteolysis of the p32 subunit, suggesting that further processing of this subunit is associated with apoptosis. Bcl-2 overexpression prevented anti- micro induction of CPP32-like activity and apoptosis, and blocked further processing of the Mch3 p32 subunit. In contrast, CD40 stimulation completely blocked the appearance of the p32 subunit in addition to blocking CPP32-like activity and apoptosis induced by BCR cross-linking. Moreover, only CD40 stimulation was able to prevent anti- micro-induced growth arrest, which was correlated with inhibition of retinoblastoma and of cyclin A down-regulation. In splenic B cells, Mch3 is also specifically proteolyzed ex vivo after induction of apoptosis by BCR cross-linking, demonstrating the specific involvement of caspase-7/Mch3 in apoptosis induced in B cell tolerance.
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PMID:Caspase activation by BCR cross-linking in immature B cells: differential effects on growth arrest and apoptosis. 1022 36

The clinical, histological, phenotypic and genotypic features of 21 primary cutaneous B-cell lymphomas (CBCLs) have been investigated. The patients were 13 men and eight women aged 34-91 years (median 67) at diagnosis. Eighteen patients had localized disease, and three had multiple skin lesions at diagnosis. Twelve patients developed cutaneous or extracutaneous recurrences, and five died from malignant lymphoma 7-84 months (median 36) after diagnosis. Histological examination showed features of marginal zone/mucosa-associated lymphoid tissue (MALT)-type lymphoma in 12 cases. Three of these had transformed to diffuse large B-cell lymphoma (DLBCL) in relapse biopsies. The remaining cases were seven primary DLBCLs and two cases tentatively classified as follicle centre cell (FCC) lymphoma. The neoplastic B cells showed similar phenotypes and genotypes in most cases (CD20+, CD79+, CD5-, CD10-, cyclin D1-, bcl-2+, bcl-x-, bax-, t(14;18)-negative). p53 protein was expressed in five cases, and four harboured mis-sense or loss-of-function mutations in the p53 gene. Deletion or promoter region hypermethylation of the p16INK4a gene was detected in two patients with DLBCL. The level of retinoblastoma protein expression and the proliferative fraction were significantly higher in DLBCL (> 50%) than in MALT- or FCC-type lymphomas (< 10%). Features associated with an unfavourable prognosis were the presence of multiple skin lesions at diagnosis, transformation from MALT-type lymphoma to DLBCL, and possibly p16INK4a aberrations. It is concluded that most CBCLs are dissimilar from FCC lymphomas and seem to be more closely related to marginal zone/MALT-type lymphomas. It is also suggested that there are fundamental differences between DLBCL and other histological categories of CBCL, indicating that cutaneous DLBCL is a separate entity with an increased growth potential and genetic features similar to DLBCL originating in other anatomical sites.
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PMID:Primary cutaneous B-cell lymphoma: a clinical, histological, phenotypic and genotypic study of 21 cases. 1080 48

The human p107 protein shares many structural and functional features with the retinoblastoma gene product and retinoblastoma-related p130 protein. In this study, we have cloned and elucidated the complete intron-exon organization of the gene encoding the p107 protein. The gene contains 22 exons spanning over 100kilobase pairs of genomic DNA. The length of individual exons ranges from 50 to 840base pairs. The arrays of exons in the p107 gene are rather similar among members of the gene family, especially to those of the p130 gene, while the length of introns is extensively diverse. This study will provide a molecular basis for implementing comprehensive screening for p107 mutations using genomic DNAs from human malignancies. We also show a detailed structure of an intragenic deletion of the p107 gene found in a human B-cell lymphoma cell line, KAL-1, which was shown to occur by homologous recombination between the two directly repeated Alu family sequences.
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PMID:Structure of the human retinoblastoma-related p107 gene and its intragenic deletion in a B-cell lymphoma cell line. 1086 94

The genetic mechanisms underlying the genesis, disease progression, and high-grade transformation of marginal zone B-cell lymphoma (MZBCL) are poorly understood. We analyzed 33 cases of histologically and immunophenotypically well-characterized MZBCL (12 extranodal, 11 nodal, and 10 splenic MZBCL; 27 at primary diagnosis and six during the course of disease) by dual-color interphase fluorescence in situ hybridization (FISH) for deletions of tumor suppressor genes. We investigated loci known to play a role in the genesis or disease progression of other subtypes of lymphoid malignancies, namely the P53 gene (17p13), the retinoblastoma gene (RB, 13q14), the D13S25 locus (13q14), and the P16(INK4A) gene (9p21). Heterozygous deletions of P53 were detected in three out of the 33 cases, including two splenic and one extranodal MZBCL. One of these patients was analyzed at primary diagnosis and two during the course of disease. Heterozygous deletions of the RB gene (nodal MZBCL) and D13S25 (splenic MZBCL) were found in one case each. P16 deletions were not detected in any of our cases. We conclude that deletions of the analyzed tumor suppressor genes are relatively rare in MZBCL, which contrasts with the findings in some other subtypes of NHL.
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PMID:Analysis of the P53, RB/D13S25, and P16 tumor suppressor genes in marginal zone B-cell lymphoma: An interphase fluorescence in situ hybridization study. 1091 69


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