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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiparameter flow cytometry may be used to detect minimal residual disease in acute leukemia because leukemic cells often display aberrant phenotypes when compared to normal cells. One limitation of this approach in B-precursor ALL is that leukemic phenotypes are often qualitatively similar to normal marrow B progenitors, though it has long been recognized that the latter show a predictable pattern of antigen expression with differentiation. In this study we used four-color flow cytometry to define precisely the patterns of normal antigen expression on a series of normal bone marrows using two different four-color combinations of antibodies: CD19-APC/CD45-perCP/CD20-PE/CD10-FITC; and CD19-APC/CD45-perCP/CD9-PE/CD34-FITC. A series of dual parameter displays were created in which normal B precursors occupied predictable regions. We then tested these antibody combinations on a series of 82 cases of B-precursor ALL and found that in 76/82 cases (93%) the first combination demonstrated an abnormal population on at least one of the dual parameter displays, and that 72/77 cases tested (94%) showed an abnormality with the second combination. When taken together, 81/82 cases (99%) showed an abnormality. When purified blasts were serially diluted into normal marrows we found a sensitivity of detection of 1 cell in 10(4) normal marrow cells provided sufficient CD19+ cells were acquired to visualize the abnormal population as a discrete cluster. Because the pattern of antigen expression in normals is very reproducible, it is possible to create a fixed set of geometrical regions to define the normal; this makes analysis of an unknown sample very straightforward. We conclude that our approach could be employed as a simple method for the detection of minimal residual disease in B-precursor ALL, and unlike many other methods should prove applicable to virtually all cases of this malignancy.
Leukemia 1999 Apr
PMID:A limited antibody panel can distinguish B-precursor acute lymphoblastic leukemia from normal B precursors with four color flow cytometry: implications for residual disease detection. 1021 62

The translocation t(11;18)(q21;q21), which is the most frequent chromosomal aberration in extranodal marginal zone B cell lymphomas of MALT-type, was characterised in a series of 34 biopsies, including 18 gastric non-Hodgkin's lymphomas (NHL) of MALT-type, six MALT-type NHL of extragastral origin and 10 extranodal large B cell lymphomas (LBL). Based on fluorescence in situ hybridisation, STS-PCR analysis and screening of genomic PAC libraries, a physical map of contiguous DNA probes on chromosome 11 was constructed containing the anti-apoptotic genes API2 and API1 adjacent to the translocation breakpoint. RACE-PCR experiments revealed MALT1 the chromosome 18-derived fusion partner of API2, which has also been reported recently by other groups. RT-PCR analysis and DNA sequencing demonstrated the expression of an API2-MALT1 fusion transcript in 18/24 gastral and extragastral MALT-type lymphomas. In none of 10 LBLs was a translocation specific RT-PCR product detected. Five variants of the fusion transcript were identified and in all instances the open reading frame of the fused portion of the MALT1 gene was maintained. The molecular analysis of these variants allowed the design of optimised assays for the diagnosis of the API2-MALT1 gene rearrangement.
Leukemia 2000 Nov
PMID:Heterogeneity of the API2-MALT1 gene rearrangement in MALT-type lymphoma. 1106 33

The t(4;11) translocation is the cytogenetic hallmark of a subset of acute lymphoblastic leukemias characterized by pro-B immunophenotype and a dismal prognosis. This translocation fuses the MLL gene on chromosome band 11q23 and the AF4 gene on 4q21, resulting in the expression of fusion transcripts from both translocated chromosomes. The MLL-AF4 chimeric transcript is thought to mediate the leukemic transformation. The MLL genomic disruption detected by Southern blot and the RT-PCR for the MLL-AF4 chimeric transcript expression are molecular evidence of this chromosomal translocation. However, similar molecular rearrangements have also been identified in cases without the cytogenetic t(4;11). We report a 30-year-old patient with high risk ALL, a normal karyotype, and molecular evidence of MLL-AF4 fusion. Using a double color FISH assay with MLL specific PAC probes, a cryptic t(4;11) due to insertion of 5' MLL sequences in chromosome 4q21 was demonstrated. Consequently the MLL-AF4 was encoded by der(4). This insertion mechanism precludes the genomic recombination of AF4-MLL and supports the crucial role played by MLL-AF4 in leukemogenesis. The findings of our case, along with others, show the importance of complementing the karyotype with molecular and FISH techniques.
Leukemia 2001 Apr
PMID:Cryptic t(4;11) encoding MLL-AF4 due to insertion of 5' MLL sequences in chromosome 4. 1136 62

Structural alterations in 3q27 affecting the BCL6 locus are among the most frequent changes in B-NHL. The aim of the present study was to establish an interphase-FISH assay for the detection of all diverse BCL6 translocations in B-NHL. Two different approaches were tested, one using a PAC-clone spanning the major breakpoint region (MBR) of BCL6 (span-assay), and another using two BAC clones flanking the MBR (flank-assay). Interphase FISH with the span-assay detected the various BCL6 translocations in seven B-NHL cell lines. The dual-color flank-assay was evaluated in two laboratories independently: in normal controls, the cutoff level for false-positive signals was 2.6%, whereas the cutoff level for false-negatives in the seven cell lines was 7.5%. To test the feasibility of the FISH strategies, 30 samples from patients with B-NHL with cytogenetic abnormalities of 3q27 were evaluated with both assays. In 21 cases, the span-assay indicated a BCL6 rearrangement. In 18 of the 21 cases, the dual-color flank-assay confirmed the translocation including 12 different partner chromosomal loci. The three false-positive cases detected with the span-assay showed trisomy of chromosome 3 by cytogenetic analyses, and they were correctly classified as non-rearranged with the flank-assay. In summary, our FISH strategy using two differently labeled flanking BCL6 BAC probes provides a robust, sensitive, and reproducible method for the detection of common and uncommon abnormalities of BCL6 gene in interphase nuclei. The routine application of this assay to patients with B-NHL will allow the assessment of the diagnostic and prognostic significance of BCL6 rearrangements.
Leukemia 2001 Sep
PMID:Detection of translocations affecting the BCL6 locus in B cell non-Hodgkin's lymphoma by interphase fluorescence in situ hybridization. 1151 11

The recently discovered MLT/MALT1 gene is fused with the API2 gene in the t(11;18)(q21;q21), which characterizes about one-third of MALT lymphomas. In order to screen for variant translocations and amplifications of MLT/MALT1, we have developed a novel, undirected two-color interphase fluorescence in situ hybridization (FISH) assay with two PAC clones flanking MLT/MALT1. This assay was applied to 108 marginal zone B-cell lymphomas (MZBCLs), including 72 extranodal MALT lymphomas, 17 nodal, and 19 splenic MZBCL. In 19 MALT lymphomas (26%), but in none of the nodal or splenic MZBCL, separated hybridization signals of the MLT/MALT1 flanking probes, were found. Further FISH analyses showed that 12 of these 19 cases displayed the classical t(11;18) and the remaining seven cases revealed the novel t(14;18)(q32;q21), involving the MLT/MALT1 and IGH genes. The frequency at which these translocations occurred varied significantly with the primary location of disease. The t(11;18) was mainly detected in gastrointestinal MALT lymphomas, whereas the t(14;18) occurred in MALT lymphomas of the parotid gland and the conjunctiva. Amplification of MLT/MALT1 was not observed in any of the lymphomas analyzed. We conclude that the translocations t(11;18)(q21;q21) and t(14;18)(q21;q32) represent the main structural aberrations involving MLT/MALT1 in MALT lymphomas, whereas true amplifications of MLT/MALT1 occur rarely in MZBCL.
Leukemia 2003 Nov
PMID:Translocations t(11;18)(q21;q21) and t(14;18)(q32;q21) are the main chromosomal abnormalities involving MLT/MALT1 in MALT lymphomas. 1293 Dec 13

The ABL tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of CML and is increasingly used in the stem cell transplantation (SCT) setting. Since ABL-dependent intracellular signaling molecules are involved in T-cell activation, imatinib may affect T-cell responses in vivo, thus affecting T-cell function in CML patients, disrupting immune reconstitution after allogeneic SCT and/or impeding the graft-versus-leukemia effect. Here we demonstrate that imatinib inhibits PHA-induced proliferation of normal peripheral blood mononuclear cells at in vitro concentrations (1-5 micromol/l) representative of the pharmacological doses used therapeutically in vivo. The effect is not dependent on antigen-presenting cells because CD3/CD28-induced T-cell stimulation was similarly inhibited by imatinib. Dose-dependent inhibition of the proliferative response of purified CD8+ and CD4+ T lymphocytes to anti-CD3/CD28 was similarly observed and associated with reduction in IFN-gamma production. The inhibitory effect could not be ascribed to an increased rate of apoptosis but the expression of activation markers on CD3+ T cells was significantly reduced in the presence of imatinib (1-5 micromol/L). Inhibition of T-cell proliferation was reversible after removal of the drug from the cultures. Thus, imatinib inhibits T-cell proliferation in vitro, an effect that is APC-independent, reversible, and does not involve apoptosis induction.
Leukemia 2004 Aug
PMID:Imatinib inhibits the activation and proliferation of normal T lymphocytes in vitro. 1567 13

Wnt signaling has recently been implicated in carcinogenesis. We studied the activity of Wnt signaling and the methylation status of WIF1, DKK3, APC, SFRP1, SFRP2, SFRP4 and SFRP5 by methylation-specific PCR in myeloma cell lines and primary myeloma samples. Of the four cell lines, Wnt signaling was constitutively activated in LP1 and WL2, correlating with hypermethylation and hence silencing. Moreover, 5-aza-2'-deoxycytidine treatment of these two cell lines showed progressive demethylation of methylated Wnt inhibitors, re-expression of transcripts and downregulation of Wnt signaling. In both LP1 and WL2 cells, multiple Wnts and Fzs were simultaneously expressed. Treatment of WL2, in which SFRP1 was completely methylated, with recombinant secreted Frizzled-related protein 1 (SFRP1) induced downregulation of Wnt signaling and inhibition of proliferation. In primary myeloma samples, 42% patients had methylation of at least one of these seven genes, of which 61.9% had > or = 2 genes methylated. In conclusion, Wnt signaling is constitutively activated in myeloma, associated with methylation silencing of one or multiple soluble Wnt antagonists. An autocrine loop regulating Wnt signaling was demonstrated in the myeloma plasma cells, in which cellular proliferation was efficiently inhibited by recombinant SFRP1. Methylation study of a panel of genes, regulating a cellular pathway instead of isolated genes, is important.
Leukemia 2007 Dec
PMID:Epigenetic dysregulation of Wnt signaling pathway in multiple myeloma. 1788 84

Nuclear localization of non-phosphorylated, active beta-catenin is a measure of Wnt pathway activation and is associated with adverse outcome in patients with acute myeloid leukemia (AML). While genetic alterations of the Wnt pathway are infrequent in AML, inhibitors of this pathway are silenced by promoter methylation in other malignanices. Leukemia cell lines were examined for Wnt pathway inhibitor methylation and total beta-catenin levels, and had frequent methylation of Wnt inhibitors and upregulated beta-catenin by Western blot and immunofluorescence. One hundred sixty-nine AML samples were examined for methylation of Wnt inhibitor genes. Diagnostic samples from 72 patients with normal cytogenetics who received standard high-dose induction chemotherapy were evaluated for associations between methylation and event-free or overall survival. Extensive methylation of Wnt pathway inhibitor genes was observed in cell lines, and 89% of primary AML samples had at least one methylated gene: DKK1 (16%), DKK3 (8%), RUNX3 (27%), sFRP1 (34%), sFRP2 (66%), sFRP4 (9%), sFRP5 (54%), SOX17 (29%), and WIF1 (32%). In contrast to epithelial tumors, methylation of APC (2%) and RASSF1A (0%) was rare. In patients with AML with normal cytogenetics, sFRP2 and sFRP5 methylation at the time of diagnosis was associated with an increased risk of relapse, and sFRP2 methylation was associated with an increased risk for death. In patients with AML: (a) there is a high frequency of Wnt pathway inhibitor methylation; (b) Wnt pathway inhibitor methylation is distinct from that observed in epithelial malignancies; and (c) methylation of sFRP2 and sFRP5 may predict adverse clinical outcome in patients with normal karyotype AML.
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PMID:Acute myeloid leukemia is characterized by Wnt pathway inhibitor promoter hypermethylation. 2079 89

Currently, clinical laboratories face increasing demand for flow cytometry testing combined with limited funding. Therefore, many laboratories search for panels that would provide sufficient immunophenotyping information and meet economical requirements. At the Flow Cytometry Laboratory, University Health Network, Toronto, ON, Canada, we apply two 10-color tubes of surface markers for diagnosis of lymphoproliferative disorders (LPDs). These tubes contain most of the mandatory B- and T-cell markers according to European Leukemia Net (www.leukemia-net.org) recommendations. The B-cell-oriented panel includes the following antibodies: Kappa-FITC/lambda-PE/CD19-ECD/CD38-PC5.5/CD20-PC7/CD34-APC/CD23 APC-AF700/CD10 APC-AF750/CD5-PB/CD45-KO. A different combination is applied to detect cytoplasmic Ig light chain expression and aberrant immunophenotype of plasma cells. The T-cell panel allows enumeration of various T- and NK-cell subsets: CD57-FITC/CD11c-PE/CD8-ECD/CD3-PC5.5/CD2-PC7/CD56-APC/CD7-APC-AF700/CD4-APC-AF750/CD5-PB/CD45-KO. The reported overall incidence of B-cell chronic LPDs presenting with more than one aberrant population is approximately 5%. Multicolor analysis facilitates the detection of multiple aberrant populations in the same sample because expression of multiple antigens can be studied simultaneously in each defined population. Examples of LPDs with multiple aberrant populations are presented.
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PMID:Immunophenotyping of selected hematologic disorders--focus on lymphoproliferative disorders with more than one malignant cell population. 2359 Jun 55

Targeting the mitotic machinery using anti-mitotic drugs for elimination of cancer cells is a century-old concept, which continues to be routinely used as a first line of treatment in the clinic. However, patient response remains unpredictable and drug resistance limits effectiveness of these drugs. Cancer cells exit from drug-induced mitotic arrest (mitotic slippage) to avoid subsequent cell death which is thought to be a major mechanism contributing to this resistance. The tumor cells that acquire resistance to anti-mitotic drugs have chromosomal instability (CIN) and are often aneuploid. In this review, we outline the key mechanisms involved in dictating the cell fate during perturbed mitosis and how these processes impede the efficacy of anti-mitotic therapies. Further, we emphasize the recent work from our laboratory, which highlights the functional role of CEP55 in protecting aneuploid cells from death. We also discuss the rationale of targeting CEP55 in vivo, which could prove to be a novel and effective therapeutic strategy for sensitizing cells to microtubule inhibitors and might offer significantly improved patient outcome. Abbreviations: APC/C: Anaphase-Promoting Complex/Cyclosome; BAD: BCL2-Associated agonist of cell Death; BAK1: BCL2 Antagonist Kinase1; BAX: BCL2-Associated X; BCL2: B-cell Chronic Lymphocytic Leukaemia (CLL)/Lymphoma 2; BH: BCL2 Homology Domain; BID: BH3-Interacting domain Death agonist; BIM: BCL2-Interacting Mediator of cell death; BUB: Budding Uninhibited by Benzimidazoles; CDC: Cell Division Cycle; CDH1: Cadherin-1; CDK1: Cyclin-Dependent Kinase 1; CEP55: Centrosomal Protein (55 KDa): CIN: Chromosomal Instability; CTA: Cancer Testis Antigen; EGR1: Early Growth Response protein 1; ERK: Extracellular Signal-Regulated Kinase; ESCRT: Endosomal Sorting Complexes Required for Transport; GIN: Genomic Instability; MAD2: Mitotic Arrest Deficient 2; MCL1: Myeloid Cell Leukemia sequence 1; MPS1: Monopolar Spindle 1 Kinase; MYT1: MYelin Transcription factor 1; PLK1: Polo Like Kinase 1; PUMA: p53-Upregulated Mediator of Apoptosis; SAC: Spindle Assembly Checkpoint; TAA: Tumor-Associated Antigen.
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PMID:Mitotic slippage: an old tale with a new twist. 3060 Oct 84


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