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

Methylprednisolone (MP) and related corticosteroids are a fundamental part of regimens used to treat lymphoma and leukemia. In many of these malignancies, oncogenic activation of C-MYC and BCL2 is seen. Abnormalities of the tumor suppressor p53, which exerts growth-suppressing and apoptosis-enhancing functions through the transcriptional regulation of downstream genes including CDKN1, GADD45, and BCL2, are also often found. The goal was to determine the modulation of expression of the oncogenes (C-MYC and BCL2), the p53 pathway described above, and the apoptosis marker TGF-beta 1 in the human Raji lymphoma following MP treatment. Raji xenografts were grown in nude mice and growth curves characterized by sequential measurement. Mice were treated daily for 8 days with MP. Tumors were harvested untreated, or at 1 or 8 days after cessation of MP treatment, and the RNA was extracted. RT-PCR was used to determine the level of mRNA expression of the genes. Tumor growth was greatly reduced in the MP-treated mice. Gene expression levels for C-MYC and BCL2 were reduced at 1 day following MP and approached control levels 8 days after MP treatment. Expression levels of p53, CDKN1, and GADD45 were moderately and coordinately decreased at 1 day after cessation of MP treatment and remained repressed a week later. TGF-beta 1 exhibited no change in expression levels. These results suggest that decreased expression of C-MYC and BCL2 may play a role in the molecular events that initiate and are responsible for the growth inhibition of Raji lymphoma xenografts by MP.
 ...
PMID:Decreased C-MYC and BCL2 expression correlates with methylprednisolone-mediated inhibition of Raji lymphoma growth. 916 90

Marginal zone B cell lymphoma (MZBCL) represents a distinct subtype of B cell non-Hodgkin's lymphoma, which has been recently recognized and defined as a disease entity. We investigated 25 cases (18 at primary diagnosis and seven during the course of disease) of MZBCL by comparative genomic hybridization (CGH) and compared these results with cytogenetic, fluorescence in situ hybridization (FISH), and Southern blot data. Twenty of the 25 cases (80%) showed gains (total 49) or losses (total 15) of genetic material. In extranodal, nodal, and splenic MZBCL, material of chromosomes 3 (52% of cases), 18 (32%), X (24%), and 1q (16%) was most frequently gained, whereas losses predominantly involved chromosomes 17 (16%) and 9 (12%). High-level amplifications involving the regions 18q21-23 and 18q21-22, respectively, were detected in two cases. Gains of chromosomes 1q and 8q and losses of chromosome 17 or 17p occurred more frequently in relapsed or progressive lymphomas. For all of the frequently affected chromosomes, CGH allowed narrowing of the relevant subregions including 3q21-23, 3q25-29 and 18q21-23. By Southern blot analysis, the BCL2, BCL6, and CMYC proto-oncogenes were found to be a part of the over-represented regions in two cases, one case, and two cases, respectively, with gains involving 18q, 3q or 8q. In 13 cases, CGH revealed chromosomal imbalances which were not detected by cytogenetic analysis but could be confirmed by FISH or Southern blot analysis in all cases investigated. On the other hand, CGH failed to detect trisomy 3, trisomy 18, and deletion 7q in three cases with a low proportion of tumor cells bearing these abnormalities, as shown by interphase FISH. The characteristic pattern of chromosomal gains and losses detected in this study confirms the distinct nature of MZBCL and may point to chromosomal regions involved in the pathogenesis of these neoplasms.
Leukemia 1997 May
PMID:Characteristic pattern of chromosomal gains and losses in marginal zone B cell lymphoma detected by comparative genomic hybridization. 918 Mar 2

We have recently developed a method to detect tumor-specific rearrangement of the IgH gene in interphase nuclei by fluorescence in situ hybridization. Tumor-specific IgH gene rearrangement is equivalent to 14q32.33 translocation. Using this approach, we detected 14q32.33 translocation in 29 of 70 patients with B-cell non-Hodgkin's lymphoma (NHL). Chromosome t(3;14) was found in 10 of these 29 patients, and were demonstrated as a fusion signal of BCL6 and VH gene probes in interphase nuclei. Furthermore, in another series of 11 patients and a NHL cell line, we demonstrated t(14;18) and t(11;14) in interphase and metaphase cells with a combination of BCL2 (or PRAD1) with IgH gene probes. Interphase FISH with lymphoma-associated gene probes is a rapid procedure for cytogenetic diagnosis of B-cell NHL.
Leukemia 1997 Apr
PMID:Rapid detection of lymphoma-specific translocations in interphase nuclei of non-Hodgkin's lymphoma by fluorescence in situ hybridization. 920 69

We report here a large series of B-cell neoplasms with regard to rearrangement of the BCL6 gene on chromosome band 3q27. Southern blot analysis using probes from the major translocation cluster (MTC) region of the BCL6 revealed rearrangement in 32 of a total of 222 patients with various subtypes of B-cell neoplasm. In non-Hodgkin's lymphoma (NHL), rearrangements of the BCL6 gene were not closely associated with a specific histopathologic subtype but distributed in subcategories in the Working Formulation. A comparative study between NHL associated either with BCL2 or BCL6 rearrangement showed that advanced disease and bone marrow involvement were more frequent in BCL2(+) NHL. In contrast, extranodal involvement was more frequently observed in the BCL6(+) NHL. The survival curve of BCL6(+) NHL was characterized by a rapid decline followed by a plateau. Of the total of 32 BCL6(+) patients, 6 carried both BCL2 and BCL6 rearrangements, and showed clinicopathological properties of follicular lymphoma. This study suggests that BCL6 rearrangement is primarily associated with large cell lymphoma, and that BCL2(-)BCL6(+) NHL could potentially be curable with modern combination chemotherapy.
Leukemia 1997 Apr
PMID:Rearrangement of the BCL6 gene in B-cell lymphoid neoplasms. 920 77

Abnormalities of chromosome 14 involving band q32.33 are among the most commonly observed cytogenetic alterations in B-cell malignancies. To assess the incidence and pathogenetic implications of 14q32.33 translocation in chronic B-cell leukemia/lymphomas, we performed fluorescence in situ hybridization (FISH) analysis with variable region (V(H)) and gamma constant region (Cgamma) gene probes in 37 patients with these disorders. Chromosome 14q32.33 translocation was detected in 2 of 18 patients with chronic lymphocytic leukemia (CLL), 1 of 2 with CLL of mixed cell types (CLL/PL), 1 of 2 with pro-lymphocytic leukemia (PLL), 5 of 6 with leukemic mantle-cell lymphoma (MCL), 2 of 7 with splenic B-cell leukemia/lymphoma of possible marginal zone origin (SBLL) and 2 with leukemic follicular lymphoma (FL). To further characterize 14q32.33 translocations in these patients, we developed a new procedure using double-color FISH with PRAD1, BCL2, V(H) and Cgamma gene probes. Chromosome t(11;14) was detected in 1 patient with CLL/PL, 1 with PLL and 5 with MCL. Chromosome t(14;18) was detected in 2 patients with FL. In a PLL patient with t(11;14), the cosmid CPP29 containing the PRAD1 gene and its 5'-flanking region split and co-localized with both Cgamma and V(H) gene probes, thus spanning the breakpoint. In CLL and SBLL patients, donor chromosomes were other than chromosomes 2, 11, 18 and 19, suggesting the involvement of a novel oncogene(s) in the pathogenesis of these diseases. Interphase FISH rapidly detected 14q32.33 translocation, t(11;14) and t(14;18) in B-cell malignancies with low mitotic activity at the single-cell level, facilitating the correlation of the molecular features of these translocations with clinical characteristics.
 ...
PMID:Detection of 14q32.33 translocation and t(11;14) in interphase nuclei of chronic B-cell leukemia/lymphomas by in situ hybridization. 921 19

Members of both the mitogen activated protein (MAP) kinase and BCL2 gene families, acting in concert with other gene products, are involved in the regulation of cell viability. However, the relationship between these families, and the signal transduction networks that control viability-regulating genes, are only beginning to be elucidated. MCL1 is a viability-promoting member of the BCL2 family that exhibits a rapid increase in expression in response to specific differentiation- and apoptosis-inducing stimuli. The signal transduction pathway involved in eliciting this increase has now been investigated. In the ML-1 human myeloblastic leukemia cell line, a rapid and sustained increase in phosphorylation of the extracellular signal-regulated kinase (ERK) members of the MAP kinase family was found to precede the increase in MCL1 expression produced by 12-O-tetradecanoylphorbol 13-acetate (TPA) or the microtubule-disrupting agents colchicine and vinblastine. ERK activation was necessary for the increase in MCL1, as inhibition of the increase in ERK phosphorylation (with the inhibitor PD 98059) prevented the increase in MCL1 expression and caused rapid cell death by apoptosis. In addition, other agents that markedly increased ERK phosphorylation (lipopolysaccharide, okadaic acid) also increased MCL1 expression. In contrast, agents that did not have this marked effect did not increase MCL1. Upstream components in this ERK-mediated pathway were also identified, where the pathway was found to be stimulated by microtubule disruption acting through protein kinase C (PKC). These results indicate that expression of the MCL1 viability-enhancing gene is regulated through a cytoskeletal disruption-induced ERK-mediated signal transduction pathway. They therefore suggest a mechanism through which the cytoskeleton and MAP kinases can exert effects on cell viability.
 ...
PMID:Expression of the antiapoptotic MCL1 gene product is regulated by a mitogen activated protein kinase-mediated pathway triggered through microtubule disruption and protein kinase C. 977 65

OCI/AML-2 acute myeloid leukemia cells were found to undergo apoptosis after treatment with y rays from a 137Cs source. Multilaser flow cytometry techniques using probes for live cell function were used to monitor the biochemical changes that occurred prior to the loss of surface membrane integrity. These showed increases in the generation of reactive oxygen species (ROS) and in the glutathione (GSH) content of irradiated cells. An additional population of cells that showed a further increase in ROS and depletion of GSH was seen in irradiated cells but not in controls. This population showed loss of mitochondrial membrane potential (deltapsim), indicative of the mitochondrial permeability transition, and exposure of phosphatidylserine on the cell surface. Increases in intracellular calcium were observed in a proportion of these low-deltapsi(m)/high-ROS cells. Similar findings were seen using the antileukemia drug cytosine arabinoside (ara-C), although cell cycle analysis showed that the loss of deltapsi(m) occurred mainly in G1 phase with ara-C treatment, and mainly in G2 phase with irradiation. Furthermore, the protective effect of overexpression of BCL2 was more pronounced after ara-C treatment than with radiation. Cells of the TP53 (formerly known as p53)-null human AML line OCI M2 showed growth arrest in G2 phase after radiation treatment, with no loss of deltapsi(m) or morphological changes indicative of apoptosis. The flavine-dependent oxidoreductase inhibitor diphenylene iodonium failed to inhibit generation of ROS in irradiated OCI/AML-2 cells, indicating that the mechanism is unlikely to involve the TP53-induced gene PIG3. These results show that oxidative stress can occur in irradiated human leukemia "blasts", and may play a direct role in radiation-induced apoptosis.
 ...
PMID:An oxidative stress-mediated death pathway in irradiated human leukemia cells mapped using multilaser flow cytometry. 984 Jan 83

We reported previously that vascular endothelial growth factor (VEGF) inhibits the apoptotic death of hematopoietic cells that is induced by exposure to ionizing radiation (O. Katoh et al., Cancer Res., 55: 5687-5692, 1995). In this study, we show that VEGF also inhibits apoptotic cell death that is induced by exposure to the chemotherapeutic drugs etoposide and doxorubicin. To elucidate the molecular mechanisms underlying this inhibitory effect of VEGF, we examined expression levels of BCL2 family proteins in CMK86, a human leukemia cell line, after treatment with VEGF. Northern blotting and immunoblotting analyses revealed that the expression level of MCL1, a member of the BCL2 family, was increased by VEGF. Moreover, to examine the effects of MCL1 on apoptotic cell death induced by exposure to etoposide, we generated a clonal U937 myeloid leukemia cell line transfected with vectors that promoted the constitutive expression of MCL1. MCL1 decreased the caspase 3 activity induced by exposure to etoposide and increased the viability of the transfected cells after etoposide exposure. Therefore, MCL1 may be involved in the inhibitory effect of VEGF on apoptotic cell death.
 ...
PMID:Vascular endothelial growth factor inhibits apoptotic death in hematopoietic cells after exposure to chemotherapeutic drugs by inducing MCL1 acting as an antiapoptotic factor. 985 95

Cells of the TP53-deficient human leukemia cell line HL60 continue to progress throughout the cell cycle and arrest in the G2/M phase during protracted exposure to exponentially decreasing low-dose-rate radiation. We have hypothesized that G2/M-phase arrest contributes to the extent of radiation-induced cell death by apoptosis as well as to overall cell killing. To test this hypothesis, we used caffeine and nocodazole to alter the duration of G2/M-phase arrest of HL60 cells exposed to exponentially decreasing low-dose-rate irradiation and measured the activity of G2/M-phase checkpoint proteins, redistribution of cells in the phases of the cell cycle, cell death by apoptosis, and overall survival after irradiation. The results from these experiments demonstrate that concomitant exposure of HL60 cells to caffeine (2 mM) during irradiation inhibited radiation-induced tyrosine 15 phosphorylation of the G2/M-phase transition checkpoint protein CDC2/p34 kinase and reduced G2/M-phase arrest by 40-46% compared to cells irradiated without caffeine. Radiation-induced apoptosis also decreased by 36-50% in cells treated with caffeine and radiation compared to cells treated with radiation alone. Radiation survival was significantly increased by exposure to caffeine. In contrast, prolongation of G2/M-phase arrest by pre-incubation with nocodazole enhanced radiation-induced apoptosis and overall radiation-induced cell killing. To further study the role of cell death by apoptosis in the response to exponentially decreasing low-dose-rate irradiation, HL60 cells were transfected with the BCL2 proto-oncogene. The extent of G2/M-phase arrest was similar for parental, neomycin-transfected control and BCL2-transfected cells during and after exponentially decreasing low-dose-rate irradiation. However, there were significant differences (P < 0.01) in the extent of radiation-induced apoptosis of parental and neomycin- and BCL2-transfected cells after irradiation, with significantly less radiation-induced apoptosis and higher overall survival in BCL2-transfected cells than similarly irradiated control cells. These data demonstrate that radiation-induced G2/M-phase arrest and subsequent induction of apoptosis play an important role in the response of HL60 cells to low-dose-rate irradiation and suggest that it may be possible to increase radiation-induced apoptosis by altering the extent of G2/M-phase arrest. These findings are clinically relevant and suggest a novel therapeutic strategy for increasing the efficacy of brachytherapy and radioimmunotherapy.
 ...
PMID:G2/M-phase arrest and death by apoptosis of HL60 cells irradiated with exponentially decreasing low-dose-rate gamma radiation. 1036 Jul 85

Diffuse large B cell lymphoma (DLBL) constitutes the greatest percentage of adult non-Hodgkin's lymphomas and represents a diverse spectrum of lymphoid neoplasms. Clinicopathologic, phenotypic and genotypic findings were correlated and compared for 63 DLBL cases to investigate whether they represent clinically relevant subtypes. They were all cyclin D1 negative and were phenotypically divided into three groups, ie group I (CD5+ type, n=11), group II (CD5- CD10+ type, n=19), and group III (CD5- CD10- type, n=33). Data were correlated by observing the respective gene rearrangement and expression of BCL2 and BCL6. In clinical aspects, the group I cases demonstrated a significantly inferior survival than those of the other two groups (log-rank test, P = 0.016). Although rearrangement of BCL2 and BCL6 did not show any inclination to a specific subgroup, the immunohistochemical detection of BCL2 was less frequent, at a statistically significant level (P=0.011), in group II (50%) than in group I (82%) and III (82%) cases. This appears to confirm the unique aspect of the CD5- CD10+ type DLBL, indicating a certain relationship with the normal germinal center cells which usually lack BCL2 expression. The BCL6 protein expression was detected in most of the present DLBL cases (92%) irrespective of this grouping. These data suggest that the phenotypic delineation by the detection of CD5 and CD10 will improve our understanding of DLBL and be helpful in a future subgrouping of DLBL.
Leukemia 1999 Sep
PMID:Molecular and immunological dissection of diffuse large B cell lymphoma: CD5+, and CD5- with CD10+ groups may constitute clinically relevant subtypes. 1048 97


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>