Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Introduction and expression of the proto-oncogene bcl-2 (B-cell lymphoma/leukemia 2) has been shown to extend the survival of certain hematopoietic cell lines after growth factor deprivation, by blocking apoptosis or programmed cell death. We investigated the effect of bcl-2 expression on cellular sensitivity to lysis by tumor necrosis factor (TNF), a cytokine capable of inducing apoptosis in several tumor cell lines. Introduction of the human bcl-2 gene in the highly TNF-sensitive L929 mouse fibrosarcoma cell line did not result in altered TNF sensitivity. Likewise, NIH3T3 and REF cells, which are resistant to TNF cytotoxicity but become TNF sensitive upon cotreatment with actinomycin D or upon expression of the adenovirus E1A gene, did not show altered TNF sensitivity upon bcl-2 transfection. Despite constitutive expression of the endogenous bcl-2 gene, human MCF7 breast carcinoma cells, as well as HL60 promyelocytic leukemia and U937 histiocytic lymphoma cell lines were found to be TNF sensitive. bcl-2-overexpressing derivatives of these cell lines did not acquire reduced TNF sensitivity and still exhibited the characteristic pattern of internucleosomal DNA fragmentation of TNF-induced apoptosis. Moreover, bcl-2 expression in the interleukin 3 (IL-3)-dependent myeloid cell line 32D protected these cells from apoptosis resulting from growth factor deprivation, but not from apoptosis induced by TNF. These data clearly establish the absence of a correlation between bcl-2 gene expression and cellular sensitivity to TNF-induced cell lysis. These findings are discussed in the context of the hypothesis of different pathways for induction of apoptosis, only some of which are affected by bcl-2 expression.
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PMID:Effect of bcl-2 proto-oncogene expression on cellular sensitivity to tumor necrosis factor-mediated cytotoxicity. 845 35

2-Chloro-2'-deoxyadenosine (CldAdo), a nucleoside that has proven useful in the treatment of several chronic lymphoid malignancies, and its analogue, 2-bromo-2'-deoxyadenosine, are both effective inhibitors of the bacterial (Escherichia coli) purine-nucleoside phosphorylase (PNP), with Ki values of 4.5 microM and 6.3 microM, respectively. The examination of a series of base-modified analogues of CldAdo has shown that several other compounds have similar inhibitor properties, and has indicated that 6-benzyloxy-2-chloro-9-(2'-deoxy-beta-D-ribofuranosyl)purine is the most potent inhibitor with a Ki value of 0.5 microM, competitive with respect to inosine (Ino). CldAdo itself and its base-modified analogues, discounting those substituted at C(8), are also substrates for the E. coli PNP and undergo rapid glycosidic bond cleavage. CldAdo is degraded with substrate efficiency, i.e. Vmax/Km similar to that observed for Ino (130%), although the individual kinetic constants, Km and Vmax, are both approximately an order of magnitude lower than for Ino. All compounds tested are totally inactive as substrates and inhibitors for mammalian (calf spleen) PNP and therefore constitute a new class of potent selective, although cleavable, inhibitors of bacterial phosphorylases. 8-Bromo-2-chloro-2'-deoxyadenosine and 8-thio-2-chloro-2'-deoxyadenosine are the only base-modified CldAdo derivatives showing inhibitory activity against MOLT-3 (acute T-cell leukemia) and U-937 (histiocytic lymphoma) cells and, as shown in this study, are resistant to degradation by E. coli PNP. The above-mentioned results suggest that both analogues could be effective as oral cytotoxic agents that are noncleavable by enteric bacteria.
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PMID:2-Chloro-2'-deoxyadenosine (cladribine) and its analogues are good substrates and potent selective inhibitors of Escherichia coli purine-nucleoside phosphorylase. 852 55

The B-cell leukemia/lymphoma-2 (bcl-2) proto-oncogene is peculiar, as its product appears to provide survival advantage to B cells by blocking apoptosis. Expression of bcl-2 protein was analyzed in 54 cases of primary non-Hodgkin's malignant lymphomas of the oral cavity by immunohistologic staining of paraffin-embedded tissue. The immunophenotype of each tumor was established with the use of a panel of monoclonal and polyclonal antibodies to lymphoid cell differentiation antigens. The cases in the present study were 42 B-cell lymphomas, 7 T-cell lymphomas and 5-lymphomas revealing histiocytic markers. Sixteen of the 42 B-cell lymphomas were positive for bcl-2 protein, and were composed of 7 low-grade B-cell lymphomas and 9 high-grade B-cell lymphomas. Seven low-grade B-cell lymphomas were composed of one mucosa-associated lymphoid tissue type, three centrocytic types and three centroblastic-centrocytic types. Nine high-grade B-cell lymphomas comprised four centroblastic types, one immunoblastic type and four lymphoblastic types. Enhanced expression of the bcl-2 oncogenic protein was detectable in lymphoma cells in 2 cases for the T-cell lymphoma, and one case for the true histiocytic lymphoma. In contrast to the previous reports of American node-based lymphomas, Japanese primary oral lymphomas in our series expressed a lower frequency of bcl-2 protein. Furthermore, the present study indicated that bcl-2 protein was expressed on a wide variety of B-cell lymphomas, T-cell lymphomas and true histiocytic lymphoma, and that differences in bcl-2 protein expression may be useful in the diagnostic separation of lymphoblastic lymphoma with B-cell marker from Burkitt's lymphoma.
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PMID:Expression of bcl-2 oncogene product in primary non-Hodgkin's malignant lymphoma of the oral cavity. 868 41

The EVI-1 gene was originally detected as an ectopic viral insertion site and encodes a nuclear zinc finger DNA-binding protein. Previous studies showed restricted EVI-1 RNA or protein expression during ontogeny; in a kidney and an endometrial carcinoma cell line; and in normal murine oocytes and kidney cells. EVI-1 expression was also detected in a subset of acute myeloid leukaemias (AMLs) and myelodysplasia. Because EVI-1 is expressed in the urogenital tract during development, we examined ovarian cancers and normal ovaries for EVI-1 RNA expression using reverse transcription polymerase chain reaction (RT-PCR) and RNAase protection. Chromosome abnormalities were examined using karyotypes and whole chromosome 3 and 3q26 fluorescence in situ hybridisation (FISH). RNA from six primary ovarian tumours, five normal ovaries and 47 tumour cell lines (25 ovarian, seven melanoma, three prostate, seven breast and one each of bladder, endometrial, lung, epidermoid and histiocytic lymphoma) was studied. Five of six primary ovarian tumours, three of five normal ovaries and 22 of 25 ovarian cell lines expressed EVI-1 RNA. A variety of other non-haematological cancers also expressed EVI-1 RNA. Immunostaining of ovarian cancer cell lines revealed nuclear EVI-1 protein. In contrast, normal ovary stained primarily within oocytes and faintly in stroma. Primary ovarian tumours showed nuclear and intense, diffuse cytoplasmic staining. Quantitation of EVI-1 RNA, performed using RNAase protection, showed ovarian carcinoma cells expressed 0 to 40 times the EVI-1 RNA in normal ovary, and 0-6 times the levels in leukaemia cell lines. Southern analyses of ovarian carcinoma cell lines showed no amplification or rearrangements involving EVI-1. In some acute leukaemias, activation of EVI-1 transcription is associated with translocations involving 3q26, the site of the EVI-1 gene. Ovarian carcinoma karyotypes showed one line with quadruplication 3(q24q27), but no other clonal structural rearrangements involving 3q26. However, whole chromsome 3 and 3q26 FISH performed on lines with high EVI-1 expression showed translocations involving chromosome 3q26. EVI-1 is overexpressed in ovarian cancer compared with normal ovaries, suggesting a role for EVI-1 in solid tumour carcinogenesis or progression. Mechanisms underlying EVI-1 overexpression remain unclear, but may include rearrangements involving chromosome 3q26.
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PMID:Expression of the zinc finger gene EVI-1 in ovarian and other cancers. 893 29

The EVI-1 gene encodes a Zn finger, DNA binding protein previously detected in some acute myelogenous leukemias (AML) and myelodysplasias (MDS), but not in normal marrow or cord blood cells. Experimental studies suggest EVI-1 blocks cellular differentiation by binding to GATA-1 or other specific DNA sequences controlling gene expression, and may be involved in the pathogenesis of some AMLs. To further define potential roles for EVI-1 in leukemia pathogenesis, we studied its regulation in acute promyelocytic leukemias (APL). Seven of 11 APL cases expressed EVI-1 RNA detected by RNA PCR at diagnosis, and expression was detected in two additional cases after treatment with all-trans retinoic acid (ATRA). Two of four cases studied at relapse also expressed EVI-1 RNA. To investigate regulation of EVI-1 expression in APL, we examined its expression in the NB4 APL cell line. NB4 cells did not express EVI-1 under basal conditions, but expressed EVI-1 after ATRA-induced differentiation. When NB4 cells were exposed to ATRA and transferred to cultures with N,N'-hexamethylene-bis-acetamide (HMBA), differentiation occurred but EVI-1 RNA was not detected, indicating that EVI-1 expression was not required for terminal, NB4 differentiation. ATRA-resistant NB4 cells were obtained by continuous culture in gradually increasing concentrations of ATRA. These cells did not express markers of differentiation but continued to express EVI-1 for several weeks even after ATRA withdrawal. To assess whether expression of the APL PML-RAR alpha fusion gene alone was sufficient for ATRA induction of EVI-1, the PML-RAR alpha gene cDNA was expressed in U937 histiocytic lymphoma cells. ATRA treatment of PML-RAR alpha-transfected or control U937 cells did not induce EVI-1 expression. In conclusion, this study demonstrates the EVI-1 gene is consistently expressed in APL cells either constitutively or after ATRA treatment. ATRA represents the first biologically active agent shown to specifically regulate EVI-1 expression in blood cells. In contrast to previous studies in AML and MDS, the pattern of EVI-1 expression suggests it may facilitate rather than inhibit myeloid differentiation during ATRA treatment. However, effects of EVI-1 expression are likely to be complex, and expression in ATRA-resistant APL cells may indicate multiple roles for this gene.
Leukemia 1997 Feb
PMID:Expression of the Zn finger gene, EVI-1, in acute promyelocytic leukemia. 900 83

Monocytes and macrophages are closely related in origin, structure and function. True histiocytic lymphoma is a neoplasm of phagocytic histiocytes and is treated as non-Hodgkin's lymphoma. Tissue involvement with myeloid leukemia, including monocytic leukemia, is called extramedullary myeloid cell tumor or granulocytic sarcoma and treated with antileukemic chemotherapy. Differentiating true histiocytic lymphoma from tissue involvement with monocytic leukemia is a rather impossible task using available morphologic, cytochemical, immunocytochemical and molecular methods. The two entities need to be unified probably more appropriately as extramedullary myeloid cell tumor of monocytic origin, and should therefore be treated as such.
Leukemia 1997 May
PMID:True histiocytic lymphoma: is it an entity? 918 Mar 4

Expression of the natural killer (NK) cell antigen CD56 is uncommon among lymphomas, and those that do are almost exclusively of non-B-cell lineage and show a predilection for the nasal and nasopharyngeal region. This study analyzes 49 cases of nonnasal CD56+ lymphomas, the largest series to date, to characterize the clinicopathologic spectrum of these rare neoplasms. All patients were Chinese. Four categories could be delineated. (1) Nasal-type NK/T cell lymphoma (n = 34) patients were adults 21 to 76 years of age (median, 50 years), including 25 men and 9 women. They presented with extranodal disease, usually in multiple sites. The commonest sites of involvement were skin, upper aerodigestive tract, testis, soft tissue, gastrointestinal tract, and spleen. Only 7 cases (21%) apparently had stage I disease. The neoplastic cells were often pleomorphic, with irregular nuclei and granular chromatin, and angiocentric growth was common. The characteristic immunophenotype was CD2+ CD3/Leu4- CD3epsilon+ CD56+, and 32 cases (94%) harbored Epstein-Barr virus (EBV). Follow-up information was available in 29 cases: 24 died at a median of 3.5 months; 3 were alive with relapse at 5 months to 2.5 years; and 2 were alive and well at 3 and 5 years, respectively. (2) Aggressive NK cell leukemia/lymphoma (n = 5) patients presented with hepatomegaly and blood/marrow involvement, sometimes accompanied by splenomegaly or lymphadenopathy. The neoplastic cells often had round nuclei and azurophilic granules in the pale cytoplasm. All cases exhibited an immunophenotype of CD2+ CD3/Leu4- CD56+ CD16- CD57- and all were EBV+. All of these patients died within 6 weeks. (3) In blastoid NK cell lymphoma (n = 2), the lymphoma cells resembled those of lymphoblastic or myeloid leukemia. One case studied for CD2 was negative and both cases were EBV-. One patient was alive with disease at 10 months and one was a recent case. (4) Other specific lymphoma types with CD56 expression (n = 8) included one case each of hepatosplenic gammadelta T-cell lymphoma and S100 protein+ T-cell lymphoproliferative disease and two cases each of T-chronic lymphocytic/prolymphocytic leukemia, lymphoblastic lymphoma, and true histiocytic lymphoma. All of these cases were EBV-. Six patients died at a median of 6.5 months. Nonnasal CD56+ lymphomas are heterogeneous, but all pursue a highly aggressive clinical course. The nasal-type NK/T-cell lymphoma and aggressive NK cell leukemia/lymphoma show distinctive clinicopathologic features and a very strong association with EBV. Blastoid NK cell lymphoma appears to be a different entity and shows no association with EBV.
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PMID:Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. 919 74

Onconase is a 12 kDa protein homologous to pancreatic RNase A isolated from amphibian oocytes which shows cytostatic and cytotoxic activity in vitro, inhibits growth of tumors in mice and is in phase III clinical trials. The present study was aimed to reveal mechanisms by which onconase perturbs the cell cycle progression. Human histiocytic lymphoma U937 cells were treated with onconase and expression of cyclins D3 and E, as well as of the cyclin-dependent kinase inhibitors (CKIs) p16INK4A, p21WAF1/CIP1 and p27KIP1 (all detected immunocytochemically) was measured by multiparameter flow cytometry, in relation to the cell cycle position. Also monitored was the status of phosphorylation of retinoblastoma protein (pRb) by a novel method utilizing mAb which specifically detects underphosphorylated pRb in individual cells. Cell incubation with 170 nM onconase for 24 h and longer led to their arrest in G1 which was accompanied by a decrease in expression of cyclin D3, no change in cyclin E, and enhanced expression of all three CKIs. pRb was underphosphorylated in the onconase arrested G1 cells but was phosphorylated in the cells that were still progressing through S and G2/M in the presence of onconase. The cytostatic effect of onconase thus appears to be mediated by downregulation of cyclin D3 combined with upregulation of p27KIP1, p16INK4A and p21WAF1/CIP1, the events which may prevent phosphorylation of pRb during G0/1 and result in cell arrest at the restriction point controlled by Cdk4/6 and D type cyclins.
Leukemia 1998 Aug
PMID:G1 arrest of U937 cells by onconase is associated with suppression of cyclin D3 expression, induction of p16INK4A, p21WAF1/CIP1 and p27KIP and decreased pRb phosphorylation. 969 79

The t(10;11)(p13;q14-21) is a non-random translocation that occurs primarily in T cell acute lymphoblastic leukemias (T-ALL), but has also been observed in leukemias and lymphomas of diverse lineages. In U937, a cell line established from a diffuse histiocytic lymphoma, a t(10;11)(p13;q14-21) fuses AF10 to CALM. AF10 is also fused to MLL by a translocation that appears quite similar at the cytogenetic level, the t(10;11)(p12;q23). Fluorescence in situ hybridization studies have demonstrated that AF10 and CALM are also involved in other hematological malignancies containing t(10;11)(p13;q21), but no data are available concerning the molecular details of AF10-CALM fusion in primary leukemias. Using RT-PCR, we amplified multiple different isoforms of AF10-CALM and CALM-AF10 fusion cDNAs from a primary T cell ALL containing a t(10;11)(p13-14;q14-21). These cDNAs arose via alternative splicing of exons from both AF10 and CALM, which we demonstrated can also occur in the native genes. We identified at least two novel AF10 exons that can be included in wild-type and fusion cDNAs. The majority of the AF10 and AF10-CALM cDNA isoforms that we identified are predicted to encode for truncated AF10 polypeptides, raising the possibility that these might have important cellular functions in normal and malignant cells, perhaps by acting as dominant negative inhibitors of full-length AF10 or related proteins.
Leukemia 1998 Sep
PMID:Alternative splicing in wild-type AF10 and CALM cDNAs and in AF10-CALM and CALM-AF10 fusion cDNAs produced by the t(10;11)(p13-14;q14-q21) suggests a potential role for truncated AF10 polypeptides. 973 89

P48 is a 48-kDa monocytic differentiation/activation factor which was originally identified in the conditioned medium of the Reh and other leukemia cell lines and has recently been shown to be a Mycoplasma fermentans gene product. Previously, conditioned medium P48 has been shown to induce differentiation of HL-60 (human promyelocytic leukemia) cells. Recently our laboratory isolated cDNA clones for P48 from Reh cells and genomic clones from Mycoplasma fermentans and expressed the recombinant protein as a maltose binding protein (MBP) fusion protein in E. coli. In this report we present the initial characterization of this recombinant P48 fusion protein (rP48-MBP). We show that rP48-MBP induces differentiation of HL-60, U937 (human histiocytic lymphoma), and M1 (mouse myeloid leukemia) cell lines. Interestingly, rP48-MBP also induces apoptosis of U937 and HL-60 cells as assessed by terminal transferase (TUNEL) assays. This is the first report of induction of apoptosis by a Mycoplasma gene product. P48 is a Mycoplasma-derived immunomodulatory molecule which has differentiation and apoptosis-inducing activities and may be important in the pathophysiology of Mycoplasma infections. The recombinant protein may be useful in studying the mechanisms of differentiation, cytokine production, and apoptosis in malignant and nonmalignant hematopoietic cells.
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PMID:Induction of leukemia cell differentiation and apoptosis by recombinant P48, a modulin derived from Mycoplasma fermentans. 1069 14


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