Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the last decades, major medical advances have been made in the understanding of cancer biology and led to the appearance of new diagnostic tools and development of innovative therapeutics. Some basic concepts in molecular medicine, oncogenes and tumour-suppressor genes are reviewed. Special topics are devoted to Ras, erbB2, p 53 and characteristical gene rearrangements, such as bcr-abl, RARA-PML, VDJ, bcl2-IgH. The greater knowledge of the molecular etiology of cancer will contribute to disease screening, diagnosis, staging and therapy, detection of residual or recurrent disease, and development of new treatments, such as gene therapy or drugs targeted to oncogene products.
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PMID:[Contribution of molecular and genetic biology in oncology]. 762 61

To evaluate CD34+ selection of peripheral blood stem cells (PBSC) as a graft for autologous transplantation. Eight relapsing follicular lymphoma (FL) patients were submitted to CD34+ autologous stem cell transplantation (ASCT). All patients received at least two front line conventional therapies; mean time to treatment failure (TTF) was 4.5 months. Patients had disseminated stage III-IV disease after a median number of 2.1 relapses. Chemotherapy and G-CSF were used as mobilization for leukapheresis. CEPRATE SC concentrator (CellPro, Inc, Bothell, WA) was used to select CD34+ cells from leukapheresis products. With a mean of 1.8 leukaphereses per patient, 8.1 x 10(8) mononuclear cells (MNCs)/kg were collected. After the selection process, the median number of MNCs was 9.4 x 10(6)/kg; 4.3 x 10(6)/kg CD34+ cells and 17 x 10(4)/kg CFU-GM, with a purity of 83.7% and a viability of 89.2%. Mbr bcl2/IgH PCR analysis of 5 grafts showed that initial buffy-coat, and CD34- fractions were negative in 3 cases and positive in 2 cases (from whom selected CD34+ fraction remained positive in 1 case). After a conditioning regimen including total body irradiation, cyclophosphamide and etoposide, CD34+ selected cells were reinfused. All patients but one had successful engraftment, median time to WBC > 1 x 10(9)/l was 12 days and platelets > 50 x 10(9)/l 17 days. No severe infectious complications were seen. After transplant, with a minimum follow up of 2 years, 5 patients are still in complete remission (CR). Three patients have relapsed after 1 year of transplant with a mean TTF of 15.6 months. We conclude that PBSC CD34+ selection for ASCT was a safe technique, capable of reconstituting hemopoiesis without severe complications for high risk FL patients included in this study. The effects of tumor cell purging need to be evaluated in a larger series.
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PMID:Peripheral blood stem cell CD34+ autologous transplant in relapsed follicular lymphoma. 908 36

The formation of the pre-B cell receptor (BCR) corresponds to an important checkpoint in B cell development that selects pro-B (pre-BI) cells expressing a functionally rearranged immunoglobulin mu (Igmu) heavy chain protein to undergo the transition to the pre-B (pre-BII) cell stage. The pre-BCR contains, in addition to Igmu, the surrogate light chains lambda5 and VpreB and the signal transducing proteins Igalpha and Igbeta. The absence of one of these pre-BCR components is known to arrest B cell development at the pre-BI cell stage. Disruption of the Pax5 gene, which codes for the B cell-specific activator protein (BSAP), also blocks adult B lymphopoiesis at the pre-BI cell stage. Moreover, expression of the mb-1 (Igalpha) gene and VH-to-DHJH recombination at the IgH locus are reduced in Pax5-deficient B lymphocytes approximately 10- and approximately 50-fold, respectively. Here we demonstrate that complementation of these deficiencies in pre-BCR components by expression of functionally rearranged Ig mu and chimeric Igmu-Igbeta transgenes fails to advance B cell development to the pre-BII cell stage in Pax5 (-/-) mice in contrast to RAG2 (-/-) mice. Furthermore, the pre-BCR is stably expressed on cultured pre-BI cells from Igmu transgenic, Pax5-deficient bone marrow, but is unable to elicit its normal signaling responses. In addition, the early developmental block is unlikely to be caused by the absence of a survival signal, as it could not be rescued by expression of a bcl2 transgene in Pax5-deficient pre-BI cells. Together, these data demonstrate that the absence of Pax5 arrests adult B lymphopoiesis at an early developmental stage that is unresponsive to pre-BCR signaling.
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PMID:Early function of Pax5 (BSAP) before the pre-B cell receptor stage of B lymphopoiesis. 970 55

In the present study the changes in the detection rate of bcl-2 and IgH gene rearrangements in relation to chemotherapy and therapeutic response in patients with diffuse large B-cell lymphoma have been investigated. Immunoglobulin gene rearrangements were detected in almost all patients during all stages of treatment. Persistence of bcl-2 rearrangements reflected the effect of chemotherapy better. Bcl-2 rearrangements were initially detected in 64% of the patients. Cells bearing the translocation disappeared during therapy in a significant group of cases. In 10 patients bcl-2-rearranged cells were detected for varying periods of time. However, no correlation was found between the molecular persistence or disappearance of cells as detected by PCR and the therapeutic response or recurrence rates.
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PMID:Investigation of the molecular changes during chemotherapy in non-Hodgkin's lymphoma. 973 9

Etoposide is among the most widely used anti-cancer drugs. Its use, however, has been associated with increased risk of secondary acute myeloid leukemia (AML) which is characterized by chromosomal translocations suggesting involvement of recombination-associated motifs at the breakpoints. A PCR-based assay was developed to quantitate the frequency of two illegitimate V(D)J recombinase-mediated genomic rearrangements-a 20-kb deletion in the hprt gene and the bcl2/IgH translocation (t(14;18)) found in non-Hodgkin's lymphoma. We examined both lymphocyte and non-lymphocyte blood cell DNA of children with acute lymphoblastic leukemia (ALL) for changes in the frequencies of these biomarkers during etoposide therapy to determine the level of illegitimate V(D)J recombination changes during therapy. A low level of t(14;18) was found in the lymphocytes before etoposide treatment, which was significantly reduced during etoposide therapy. In before-etoposide samples, no t(14;18) were found among 7.72x107 non-lymphocytes; during treatment none were found among 1.87x108 non-lymphocytes. Deletions were not found before etoposide treatment in either the lymphocytes (6.67x107) or non-lymphocytes (5.43x107) and were non-significantly elevated during etoposide therapy (1 in 1.4x108 lymphocytes and 1 in 1.39x108 non-lymphocytes). It is interesting to note the one patient with an hprt deletion mutation in non-lymphocytes; V(D)J recombination is not normally found in this cell type, but is the cell type from which AML derives. Several patients had clones of t(14;18)-bearing cells as determined by DNA sequence analysis. These results suggest that this etoposide-based chemotherapy was ineffective in producing genomic rearrangements mediated by illegitimate V(D)J recombination in these patients.
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PMID:The frequency of illegitimate V(D)J recombinase-mediated mutations in children treated with etoposide-containing antileukemic therapy. 980 12

We report the establishment and characterization of two cell lines, MEC1 and MEC2, that grew spontaneously on two subsequent occasions from the peripheral blood (PB) of a patient with B-chronic lymphocytic leukemia (B-CLL) in prolymphocytoid transformation. The patient was EBV-seropositive, his leukemic cells were EBNA negative, but the spontaneously grown cell lines are EBNA-2 positive. In liquid culture MEC1 cells grow adherent to the vessel wall and as tiny clumps; MEC2 cells do not adhere and form large clumps. The doubling time of MEC1 is 40h and of MEC2 is 31h. Both cell lines express the same light (kappa) and heavy chains (mu, delta) as the fresh parental B-CLL cells at the same high intensity, share the expression of mature B cell markers (CD19, CD20, CD21, CD22), differ in the expression of CD23 and FMC7, are CD11a+, CD18+, CD44+, CD49d+, CD54+ and express at high levels both CD80 and CD86. CD5 is negative on MEC1 cells (as on the vast majority of parental cells) and it has been lost by MEC2 cells after several months of culture. The cells have a complex karyotype. The tumour origin of MEC1 and MEC2 has been demonstrated by Southern blot analysis of the IgH loci and by Ig gene DNA sequencing. They use the VH4 Ig family and have not undergone somatic mutations (94.8% homology with germline Ig gene 4-59). Cytofluorographic analysis and RT-PCR reveal that MEC1 and MEC2 overexpress Bcl-2 together with Bax, express large amounts of Bcl-xL and trace amounts of Bcl-xS.
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PMID:MEC1 and MEC2: two new cell lines derived from B-chronic lymphocytic leukaemia in prolymphocytoid transformation. 1007 Nov 28

We report the results of high-dose chemoradiotherapy and anti-B-cell monoclonal antibody-purged autologous bone marrow transplantation (ABMT) in patients with relapsed indolent follicular lymphoma. Between March 1985 and May 1995, 153 patients underwent ABMT using a uniform ablative regimen with cyclophosphamide and total body irradiation and bone marrow (BM) purging. All patients received multiple chemotherapy regimens before ABMT. At BM harvest, only 30% of patients were in complete remission, and overt BM infiltration was present in 47%. The disease-free survival (DFS) and overall survival (OS) are estimated to be 42% and 66% at 8 years, respectively. Patients whose BM was negative by polymerase chain reaction (PCR) for bcl2/IgH rearrangement after purging experienced longer freedom from recurrence than those whose BM remained PCR positive (P <.0001). Continued PCR negativity in follow-up BM samples was also strongly predictive of continued complete remission (CR). The 12-year survival from diagnosis for these 153 patients is 69%. Considering that the median survival from diagnosis and first recurrence of patients with advanced follicular lymphoma are 8 and 5 years, respectively, our results provide evidence that myeloablative therapy and ABMT may prolong overall survival.
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PMID:Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. 1055 41

Bcl-2, the gene over-expressed in follicular lymphomas (FL), is able to block chemotherapy-induced apoptosis. Consequently, we wondered whether bcl-2/IgH expression variations during treatment of FL could predict the outcome of patients with t(14;18)-bearing FL. For this purpose, we used a reverse transcription polymerase chain reaction (RT-PCR) assay to analyse 180 serial peripheral blood samples (PBS) during 34 treatment phases in 25 patients with t(14;18)-bearing FL. In all patients but two, bcl-2/IgH gene expression was demonstrated in pre-treatment samples. During 16 out of the 34 treatment phases (47%), bcl-2/IgH expression became negative: all but one were responders to chemotherapy. This conversion was transient in six cases. In 18 treatment phases, bcl2/IgH expression remained detectable: eight were clinically considered as treatment failures, while eight others achieved PR and two achieved CR. We observed a significant correlation between treatment response and RNA PCR results (P = 0.002). Three-year overall survival of patients with stable bcl2/IgH-negative conversion was 100% compared to 54% for the remaining patients (P = 0.069); 3-year freedom from progression was respectively 87.5% and 13% (P = 0.005). These results indicate a correlation between bcl-2/IgH expression variations and both clinical response and outcome. Whether this might predict disease outcome early remains to be confirmed.
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PMID:Evolution of BCL-2/IgH hybrid gene RNA expression during treatment of T(14;18)-bearing follicular lymphomas. 1055 59

Translocation t(14; 18) has been observed in 50-85% of follicular and in 30% of diffuse non-Hodgkin lymphomas. About half of follicle center lymphoma (FCL) undergo histological conversion at relapse to more aggressive diffuse large B-cell lymphoma (DLBCL). This report correlates the molecular bcl-2/IgH rearrangement by PCR and Bcl-2 immunohistochemical (IHC) expression in a series of high grade DLBCLs with and without FCL remnant. Twenty-three paraffin-embedded lymph nodes from DLBCL patients were analyzed. Eleven patients showed FCL remnant (Group A) and 12, did not (Group B). Single PCR from paraffin extracted DNA followed by Southern transfer of products, hybridisation with internal oligoprobes for the MBR/JH and MCR/JH bcl-2 rearrangements and IHC analysis of Bcl-2 expression, were performed. PCR analysis was positive in 34.8% of patients. Bcl-2/IgH gene rearrangements were observed in 8 (34%) cases and 7 (30%) showed Bcl-2 expression on large noncleaved B-cells (centroblasts). All patients from Group A showed IHC positive reaction on FCL remnant (small cleaved cells) but only 2 (18%) were positive in DLBCL areas, suggesting either the loss of the bcl-2 expression on the transformed lymphoma, or, alternatively, the development of a second disease when the first lymphoma transforms. Group B patients showed a clear correlation between PCR and IHC studies. Our results suggest a similar frequency of t(14; 18) in DLBCLs to that reported in Europe and USA series. The discordance observed between PCR and IHC, particularly in Group A, points out the necessity to perform both studies in order to detect bcl-2 gene involvement in DLBCLs.
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PMID:Bcl-2 molecular analysis in paraffin-embedded biopsies from diffuse large B-cell lymphomas. 1105 Aug 5

Minimal residual disease (MRD) following sequential administration of CHOP and rituximab was studied in previously untreated patients with follicular lymphoma. At diagnosis, the presence of Bcl-2/IgH-positive cells in the peripheral blood (PB) and/or bone marrow (BM) was demonstrated in all patients (n = 128) by polymerase chain reaction (PCR) analysis. Patients who achieved a clinical response following CHOP but remained PCR-positive were eligible for rituximab (375 mg/m(2) intravenously, weekly for 4 weeks). After CHOP, 57% achieved a complete response (CR), 37% a partial response (PR), and 6% were nonresponders (NR). At this stage, patients proving PCR-negative (n = 41) or failing to achieve a clinical response (n = 8) were excluded from rituximab treatment. Seventy-seven patients received rituximab and entered a scheduled MRD follow-up program. At the first molecular follow-up (+12 weeks), 59% had converted to PCR negativity in the BM and PB, with a further increase documented at the second control (+28 weeks) with 74% PCR negative. At the last molecular follow-up (+44 weeks), 63% of the patients remained PCR negative. At 3 years, the estimated overall survival of all patients is 95% (95% confidence interval [CI], 86-98). For patients achieving PCR-negative status following CHOP and therefore excluded from rituximab treatment, freedom from recurrence (FFR) was 52% (95% CI, 28-71). For patients treated with rituximab, a durable PCR-negative status was associated with a better clinical outcome since FFR was 57% (95% CI, 23-81) compared with 20% (95% CI, 4-46) in patients who never achieved or lost the molecular negativity (P <.001).
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PMID:Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma. 1180 87


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