Publications by authors named "Birg F"

Tyrosine kinases activated by mutation or translocation are involved in the chronic phase of myeloproliferative disorders. Complementary or alternative events are not so well characterized. We report here a case of t(8;13) generating a ZNF198-FGFR1 fusion kinase gene on the derivative chromosome 13.

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We used a combination of DNA-microarray and tissue-microarray (TMA) analyses to identify markers that could be routinely used to predict the outcome of diffuse large-B-cell lymphoma (DLCL) patients. Gene expression profiling was performed using DNA-microarrays on 52 tumour biopsy samples [31 DLCL and 21 follicular lymphomas (FL)] from 48 patients (28 DLCL and 20 FL). T-cell leukemia/lymphoma-1A (TCL1A) mRNA overexpression was correlated with relapse in DLCL patients.

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Conventional cytogenetic analysis currently stratifies acute myelogenous leukaemia (AML) into prognostically relevant groups. However, approximately 50% of adult AMLs have normal cytogenetics (NC-AMLs), and represent a heterogeneous and poorly understood group. We analysed gene expression in 55 AML samples including 53 cases from adult patients with NC-AML (n = 36), trisomy 8, t(15;17), t(8;21), t(11;19), 7q deletion, and two cell lines using 9000-gene DNA microarrays.

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We report a novel fusion of the MYST4 and CBP genes in an acute myeloid leukaemia (AML)-M4 patient exhibiting t(10;16)(q22;p13) and t(11;17)(q23;q21). The t(10;16)(q22;p13) resulted in a rearrangement, where MYST4-CBP and CBP-MYST4 chimaeric transcripts were products of in-frame fusions of MYST4 exon 17 to CBP exon 6 and CBP exon 4 to MYST4 exon 18 respectively. The potential resulting chimaeric proteins showed similarities with MYST3-CBP, MYST3-P300 and MYST3-NCOA2 putative fusion proteins found in other cases of AML.

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The localization of caspases and their substrates in different cellular compartments may be one way to regulate apoptosis. Caspase-3-dependent proteolysis of inhibitor caspase-activated deoxyribonuclease (ICAD) activates caspase-activated deoxyribonuclease (CAD), which induces apoptotic internucleosomal DNA degradation. The nuclear localization of ICAD, pro- and active-caspase-3 molecules remains a controversial issue.

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Although the prognosis of Hodgkin's disease is relatively good, around 20% of patients do not benefit from current therapies and succumb to their disease. A large-scale molecular characterization of disease might help improve HD management. Using cDNA arrays, we studied the mRNA expression levels of approximately 1000 selected genes in 34 benign and malignant lymphoid samples including 21 classical Hodgkin's disease (HD) tissue samples.

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Microarray technology has recently led to the identification of molecular prognostic subgroups in non Hodgkin's lymphomas. In order to determine the usefulness of ready-made macroarrays as routine diagnosis tools in haemato-pathology, we have analysed lymph node biopsies using a cDNA macroarray containing genes involved in apoptosis, including caspases. Nine biopsy specimens were analysed on total frozen tissues: 4 samples of B-cell follicular lymphoma (FL), two of B-cell diffuse large cell lymphoma (DLCL), and three of non-neoplastic lymph nodes from benign lymphadenitis.

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Caspases play a crucial role as apoptotic effectors; their potential implication in tumorigenesis remains to be clarified. We investigated the expression and function of caspases 7, 8, and 9 in colon cancer tissues and cell lines. Immunohistochemistry (IHC) showed downregulation of caspase 7 (22 of 26 cases) and caspase 9 (12 of 26 cases) in colonic cancer samples compared with normal mucosa on the same tissue section.

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The present review focuses on recent insights into the regulation of caspases by other components of the apoptotic pathway, including the mechanisms by which caspase activation influence the death of lymphoma cells. In the light of our recent findings and similar observations of other investigators, it is likely that lymphoma cells possess the complete caspase machinery required for the apoptotic process. Inhibition of caspases activation appears as a potential mechanism to explain apoptotic defects of malignant B-cells, and thus may constitute the basis for new cancer therapies.

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Aims: Microarray technology has recently led to the identification of molecular prognostic subgroups in non-Hodgkin's lymphomas. To determine the usefulness of ready made macroarrays as routine diagnostic tools in haematopathology, lymph node biopsies were analysed using a cDNA macroarray containing genes involved in apoptosis, including caspases.

Methods: Nine biopsy specimens were analysed using total frozen tissues: four samples of B cell follicular lymphoma, two of B cell diffuse large cell lymphoma, and three of non-neoplastic lymph nodes from benign lymphadenitis.

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Lymphoma cells often display in vitro resistance to FAS-induced apoptosis, in which caspases act as crucial cell death effectors. Following FAS stimulation, caspase-8 activates caspase-3, which in turn activates the caspase-activated DNAse (CAD) by proteolysis of its inhibitor (ICAD). To investigate the mechanism of FAS resistance, the expression of caspase-8 was analysed by immunohistochemistry, together with that of the substrates caspase-3 and ICAD, in 52 representative samples from non Hodgkin's lymphoma (NHL), 12 from Hodgkin's disease (HD), and eight benign lymphoid tissues.

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Acute promyelocytic leukemia (APL) is typified by the t(15;17), generating the PML-RAR alpha fusion and predicting a beneficial response to retinoids. However, a sizeable minority of APL cases lack the classic t(15;17), prompting the establishment of the European Working Party to further characterize this group. Such cases were referred to a workshop held in Monza, Italy and subjected to morphologic, cytogenetic, and molecular review, yielding 60 evaluable patients.

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Acute promyelocytic leukemia (APL) is typified by the t(15;17) translocation, which leads to the formation of the PML/RARA fusion gene and predicts a beneficial response to retinoids. However, approximately 10% of all APL cases lack the classic t(15;17). This group includes (1) cases with cryptic PML/RARA gene rearrangements and t(5;17) that leads to the NPM/RARA fusion gene, which are retinoid-responsive, and (2) cases with t(11;17)(q23;q21) that are associated with the PLZF/RARA fusion gene, which are retinoid-resistant.

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A paraHox gene cluster has been described recently in Amphioxus. We show here using bioinformatics and cytogenetics that, as the probable result of the duplication of an ancestral paraHox gene cluster, human paraHOX genes are located in four paralogous regions of the genome, on chromosomes 4, 5, 13 and X. By analogy with the four HOX gene clusters, we propose to designate the four paraHOX gene clusters as paraHOX-A to D clusters.

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Most technical strategies for the analysis of gene expression in tissues are able to study only one protein or RNA product at the same time. A new recent method referred to as <> or <> is able to analyze simultaneously several hundreds of different genes. The DNA array is a nylon membrane on which are spotted equal amounts of cDNAs corresponding to different genes.

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To determine whether the expression levels of Bcl-2 family apoptotic regulators are correlated with the histopathological heterogeneity of B cell non-Hodgkin's lymphomas (NHL), we quantified their expression in malignant B cell populations isolated from 33 biopsy samples, including small lymphocytic lymphoma (SLL, n = 9), mantle cell lymphoma (MCL, n = 8), follicular lymphoma (FL, n = 8), and diffuse large cell lymphoma (DLCL, n = 8). Normal B cells purified from reactive lymph nodes and tonsil (n = 3) were used as controls. Cell lysates were analyzed by Western blotting, and signals quantified by densitometry.

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We have previously shown that malignant B cells from non-Hodgkin's lymphomas (NHL) are resistant to Fas-mediated apoptosis. To determine the mechanisms underlying this resistance, we analysed by Western blotting the expression of several apoptotic regulators, caspase 3, caspase 8, FADD and poly(ADP-ribose) polymerase (PARP) in fresh lymphoma cells, isolated from 16 B-NHL biopsy samples of different histological subtypes, and displaying variable levels of Fas expression. The profiles of expression of these apoptotic regulators were monitored in cell lysates at different times following Fas with or without CD40 stimulation.

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Typical acute promyelocytic leukemia (APL) is associated with the t(15;17) translocation, expression of a PML/RARA fusion transcript, and responsiveness to all-trans retinoic acid (ATRA). Rare APL cases implicating the RARA but not the PML gene have been reported. Cases with t(11;17)(q23;q21) which fuses the PLZF and RARA genes do not respond to ATRA.

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Conventional chromosome analysis (CCA) and interphase fluorescence in situ hybridization (FISH) was performed in 42 patients with mantle-cell lymphoma (MCL), with BCL1 rearrangement. The t(11;14)(q13;q32) or 11q abnormalities were detected by CCA in 34 cases, 20 of which had additional aberrations. A normal karyotype was observed in 8 cases.

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We report on the molecular characterization of two acute myeloid leukemias (AML), one AML-M1 (patient 1) and one AML-M2 (patient 2) with t(8;21)(p21;q22) and t(8;20)(q22;p13), respectively, at diagnosis. The locations of the breakpoints, 21q22 in patient 1 and 8q22 in patient 2, prompted us to search for a cryptic t(8;21)(q22;q22) and involvement of the AML1 and ETO genes. Dual-color fluorescence in situ hybridization (FISH) using whole chromosome painting probes for chromosomes 8, 20, and 21 confirmed the conventional cytogenetic karyotypes.

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BAX, a heterodimer partner of BCL-2, is an apoptosis inducer. We aimed to characterize the distribution of the BAX protein in normal adult human tissues using immunohistochemistry (IHC). The monoclonal antibody anti-BAX 4F11 was used on paraffin sections: immunodetection of BCL-2 was performed simultaneously on serial sections.

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Using the LXSN backbone, a defective retroviral vector (LISN) was constructed that encodes the human interferon (IFN)-alpha2 (hIFN-alpha2) gene and the neomycin resistance gene; the hIFN-alpha2 gene was cloned from human placental genomic DNA. High titers of the LISN retrovirus were produced by the amphotropic packaging cell line GP+envAM12. LISN is able to infect three human hematopoietic and leukemic cell lines: K562, LAMA-84, and TF-1.

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The Fas receptor (APO-1/CD95) is capable of inducing apoptosis of lymphoid cells and is expressed in some non-Hodgkin's lymphomas (NHLs). Fas expression is up-regulated at the surface of normal B cells upon triggering of the CD40 receptor. In this report, we investigated the sensitivity of NHLs to Fas-mediated apoptosis induced by anti-Fas monoclonal antibodies (MAbs) and its possible modulation by CD40 ligation in 18 NHL biopsy samples of various histological subtypes.

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Acute promyelocytic leukemia (APL) is characterized by the t(15;17) cytogenetic abnormality leading to the expression of two fusion genes, PML/RARA and RARA/PML, and by its sensitivity to all-trans retinoic acid (ATRA) differentiating treatment. Rare APL cases lacking the t(15;17) have been described. We have previously reported two cases presenting with submicroscopic insertions of RARA or PML into chromosome 15 or 17, respectively.

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The BCL-X gene belongs to the family of BCL-2 homologues and plays an important role in the regulation of programmed cell death (PCD) in normal lymphoid tissues. BCL-X is transcribed into 2 mRNAs through alternative splicing. The protein product of the larger BCL-X mRNA (BCL-XL) functions as a PCD repressor.

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