18 results on '"Finalet Ferreiro, Julio"'
Search Results
2. Identification of distinct subgroups of EBV-positive post-transplant diffuse large B-cell lymphoma
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Morscio, Julie, Finalet Ferreiro, Julio, Vander Borght, Sara, Bittoun, Emilie, Gheysens, Olivier, Dierickx, Daan, Verhoef, Gregor, Wlodarska, Iwona, and Tousseyn, Thomas
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- 2017
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3. The landscape of copy number variations in classical Hodgkin lymphoma: a joint KU Leuven and LYSA study on cell-free DNA.
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UCL - (MGD) Service d'hématologie, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, Buedts, Lieselot, Wlodarska, Iwona, Finalet-Ferreiro, Julio, Gheysens, Olivier, Dehaspe, Luc, Tousseyn, Thomas, Fornecker, Luc-Matthieu, Lazarovici, Julien, Casasnovas, René-Olivier, Gac, Anne-Claire, Bonnet, Christophe, Bouabdallah, Kamal, Copie-Bergman, Christiane, Fabiani, Bettina, Dierickx, Daan, Marcelis, Lukas, Vermeesch, Joris, André, Marc, Vandenberghe, Peter, UCL - (MGD) Service d'hématologie, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, Buedts, Lieselot, Wlodarska, Iwona, Finalet-Ferreiro, Julio, Gheysens, Olivier, Dehaspe, Luc, Tousseyn, Thomas, Fornecker, Luc-Matthieu, Lazarovici, Julien, Casasnovas, René-Olivier, Gac, Anne-Claire, Bonnet, Christophe, Bouabdallah, Kamal, Copie-Bergman, Christiane, Fabiani, Bettina, Dierickx, Daan, Marcelis, Lukas, Vermeesch, Joris, André, Marc, and Vandenberghe, Peter
- Abstract
The low abundance of Hodgkin/Reed-Sternberg (HRS) cells in lymph node biopsies in classical Hodgkin lymphoma (cHL) complicates the analysis of somatic genetic alterations in HRS cells. As circulating cell-free DNA (cfDNA) contains circulating tumor DNA (ctDNA) from HRS cells, we prospectively collected cfDNA from 177 patients with newly diagnosed, mostly early-stage cHL in a monocentric study at Leuven, Belgium (n = 59) and the multicentric BREACH study by Lymphoma Study Association (n = 118). To catalog the patterns and frequencies of genomic copy number aberrations (CNAs), cfDNA was sequenced at low coverage (0.26×), and data were analyzed with ichorCNA to yield read depth-based copy number profiles and estimated clonal fractions in cfDNA. At diagnosis, the cfDNA concentration, estimated clonal fraction, and ctDNA concentration were significantly higher in cHL cases than controls. More than 90% of patients exhibited CNAs in cfDNA. The most frequent gains encompassed 2p16 (69%), 5p14 (50%), 12q13 (50%), 9p24 (50%), 5q (44%), 17q (43%), 2q (41%). Losses mostly affected 13q (57%), 6q25-q27 (55%), 4q35 (50%), 11q23 (44%), 8p21 (43%). In addition, we identified loss of 3p13-p26 and of 12q21-q24 and gain of 15q21-q26 as novel recurrent CNAs in cHL. At diagnosis, ctDNA concentration was associated with advanced disease, male sex, extensive nodal disease, elevated erythrocyte sedimentation rate, metabolic tumor volume, and HRS cell burden. CNAs and ctDNA rapidly diminished upon treatment initiation, and persistence of CNAs was associated with increased probability of relapse. This study endorses the development of ctDNA as gateway to the HRS genome and substrate for early disease response evaluation.
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- 2021
4. Unraveling the Landscape of Copy Number Aberrations in Hodgkin Lymphoma: A Joint KU Leuven and Lysa Study on Circulating Cell Free DNA
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Buedts, Lieselot, primary, Fornecker, Luc Mathieu, additional, Finalet-Ferreiro, Julio, additional, Dehaspe, Luc, additional, Tousseyn, Thomas, additional, Gheysens, Olivier, additional, Lazarovici, Julien, additional, Casasnovas, Rene-Olivier, additional, Copie, Christiane, additional, Verhoef, Gregor, additional, Smits, Sanne, additional, Vermeesch, Joris, additional, Andre, Marc, additional, and Vandenberghe, Peter, additional
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- 2018
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5. Genetic and microscopic assessment of the human chemotherapy-exposed placenta reveals possible pathways contributive to fetal growth restriction
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UCL - (SLuc) Service d'obstétrique, UCL - SSS/IREC/SLUC - Pôle St.-Luc, Verheecke, Magali, Cortés-Calabuig, Álvaro, Finalet Ferreiro, Julio, Brys, Vanessaa, Van Bree, Rita, Verbist, Godelive, Everaert, Tina, Leemans, Liesbeth, Mhallem Gziri, Mina, Boere, Ingrid, Halaska, Michael Jiri, Vanhoudt, Jeroen, Amant, Frééric, Van Calsteren, Kristel, UCL - (SLuc) Service d'obstétrique, UCL - SSS/IREC/SLUC - Pôle St.-Luc, Verheecke, Magali, Cortés-Calabuig, Álvaro, Finalet Ferreiro, Julio, Brys, Vanessaa, Van Bree, Rita, Verbist, Godelive, Everaert, Tina, Leemans, Liesbeth, Mhallem Gziri, Mina, Boere, Ingrid, Halaska, Michael Jiri, Vanhoudt, Jeroen, Amant, Frééric, and Van Calsteren, Kristel
- Abstract
INTRODUCTION: Fetal growth restriction (FGR) carries an increased risk of perinatal mortality and morbidity. A major cause of FGR is placental insufficiency. After in utero chemotherapy-exposure, an increased incidence of FGR has been reported. In a prospective cohort study we aimed to explore which pathways may contribute to chemotherapy-associated FGR. METHODS: Placental biopsies were collected from 25 cancer patients treated with chemotherapy during pregnancy, and from 66 control patients. Differentially expressed pathways between chemotherapy-exposed patients and controls were examined by whole transcriptome shotgun sequencing (WTSS) and Ingenuity Pathway Analysis (IPA). Immunohistochemical studies for 8-OHdG and eNOS (oxidative DNA damage), proliferation (PCNA) and apoptosis (Cleaved Caspase 3) were performed. The expression level of eNOS, PCNA and IGFBP6 was verified by real-time quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR). RESULTS: Most differential expressed genes between chemotherapy-exposed patients and controls were related to growth, developmental processes, and radical scavenging networks. The duration of chemotherapy exposure had an additional impact on the expression of genes related to the superoxide radicals degeneration network. Immunohistochemical analyses showed a significantly increased expression of 8-OHdG (P = 0.003) and a decreased expression of eNOS (P=0.015) in the syncytiotrophoblast of the placenta of cancer patients. A decreased expression of PCNA was detected by immunohistochemistry as RT-qPCR (NS). CONCLUSION: Chemotherapy exposure during pregnancy results in an increase of oxidative DNA damage and might impact the placental cellular growth and development, resulting in an increased incidence of FGR in this specific population. Further large prospective cohort studies and longitudinal statistical analyses are needed.
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- 2018
6. ALK-positive anaplastic large cell lymphoma with the variant RNF213-, ATIC- and TPM3-ALK fusions is characterized by copy number gain of the rearranged ALK gene
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van de Krogt, Jo-Anne, Vanden Bempt, Marlies, Finalet Ferreiro, Julio, Mentens, Nicole, Jacobs, Kris, Pluys, Ursula, Doms, Kathleen, Geerdens, Ellen, Uyttebroeck, Anne, Pierre, Pascal, Michaux, Lucienne, Devos, Timothy, Vandenberghe, Peter, Tousseyn, Thomas, Cools, Jan, and Wlodarska, Iwona
- Subjects
hemic and lymphatic diseases - Abstract
ALK positive anaplastic large cell lymphoma is characterized by 2p23/ALK aberrations, including the classic t(2;5)(p23;q35)/NPM1-ALK rearrangement present in ~80% of cases and several variant t(2p23/ALK) occurring in the remaining cases. The ALK fusion partners play a key role in the constitutive activation of the chimeric protein and its subcellular localization. Using various molecular technologies, we have characterized ALK fusions in eight recently diagnosed anaplastic large cell lymphoma cases with cytoplasmic-only ALK expression. The identified partner genes included EEF1G (one case), RNF213/ALO17 (one case), ATIC (four cases) and TPM3 (two cases). Notably, all cases showed copy number gain of the rearranged ALK gene, which is never observed in NPM1-ALK-positive lymphomas. We hypothesized that this could be due to lower expression levels and/or lower oncogenic potential of the variant ALK fusions. Indeed, all partner genes, except EEF1G, showed lower expression in normal and malignant T cells, in comparison with NPM1. In addition, we investigated the transformation potential of endogenous Npm1-Alk and Atic-Alk fusions generated by CRISPR/Cas9 genome editing in Ba/F3 cells. We found that Npm1-Alk has a stronger transformation potential than Atic-Alk, and we observed a subclonal gain of Atic-Alk after a longer culture period, which was not observed for Npm1-Alk. Taken together, our data illustrate that lymphomas driven by the variant ATIC-ALK fusion (and likely by RNF213-ALK, and TPM3-ALK), but not the classic NPM1-ALK, require an increased dosage of the ALK hybrid gene to compensate for the relatively low and insufficient expression and signaling properties of the chimeric gene. ispartof: Haematologica vol:102 issue:9 pages:1605-1616 ispartof: location:Italy status: published
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- 2017
7. Genomic alterations of the JAK2 and PDL loci occur in a broad spectrum of lymphoid malignancies
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Van Roosbroeck, Katrien, Finalet Ferreiro, Julio, Tousseyn, Thomas, van der Krogt, Jo-Anne, Michaux, Lucienne, Pienkowska-Grela, Barbara, Theate, Ivan, De Paepe, Pascale, Dierickx, Daan, Doyen, Chantal, Put, Natalie, Cools, Jan, Vandenberghe, Peter, and Wlodarska, Iwona
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hemic and lymphatic diseases - Abstract
The recurrent 9p24.1 aberrations in lymphoid malignancies potentially involving four cancer-related and druggable genes (JAK2, CD274/PDL1, PDCD1LG2/PDL2, and KDM4C/JMJD2Cl) are incompletely characterized. To gain more insight into the anatomy of these abnormalities, at first we studied 9p24.1 alterations in 18 leukemia/lymphoma cases using cytogenetic and molecular techniques. The aberrations comprised structural (nine cases) and numerical (nine cases) alterations. The former lesions were heterogeneous but shared a common breakpoint region of 200 kb downstream of JAK2. The rearrangements predominantly targeted the PDL locus. We have identified five potential partner genes of PDL1/2: PHACTR4 (1p34), N4BP2 (4p14), EEF1A1 (6q13), AK2 (9p24.1), and IGL (22q11). Interestingly, the cryptic JAK2-PDL1 rearrangement was generated by a microdeletion spanning the 3'JAK2-5'PDL1 region. JAK2 was additionally involved in a cytogenetically cryptic IGH-mediated t(9;14)(p24.1;q32) found in two patients. This rare but likely underestimated rearrangement highlights the essential role of JAK2 in B-cell neoplasms. Cases with amplification of 9p24.1 were diagnosed as primary mediastinal B-cell lymphoma (five cases) and T-cell lymphoma (four cases). The smallest amplified 9p24.1 region was restricted to the JAK2-PDL1/2-RANBP6 interval. In the next step, we screened 200 cases of classical Hodgkin lymphoma by interphase FISH and identified PDL1/2 rearrangement (CIITA- and IGH-negative) in four cases (2%), what is a novel finding. Forty (25%) cases revealed high level amplification of 9p24.1, including four cases with a selective amplification of PDL1/2. Altogether, the majority of 9p24.1 rearrangements occurring in lymphoid malignancies seem to target the programmed death-1 ligands, what potentiates the therapeutic activity of PD-1 blockade in these tumors. © 2016 Wiley Periodicals, Inc. ispartof: Genes, Chromosomes & Cancer vol:55 issue:5 pages:428-441 ispartof: location:United States status: published
- Published
- 2016
8. ALK-Positive Anaplastic Large Cell Lymphoma with the Variant EEF1G-, RNF213- and Atic-ALK Fusions Is Featured By Copy Number Gain of the Rearranged ALK Gene
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Wlodarska, Iwona, primary, van der Krogt, Jo-Anne, additional, Finalet Ferreiro, Julio, additional, Kris, Jacobs, additional, Ellen, Geerdens, additional, Uyttebroeck, Anne, additional, Vandenberghe, Peter, additional, Tousseyn, Thomas, additional, and Cools, Jan, additional
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- 2015
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9. Involvement of FER and FES in the Pathogenesis of Follicular Variant of Peripheral T-Cell Lymphoma
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Wlodarska, Iwona, primary, van der Krogt, Jo-Anne, additional, Van Roosbroeck, Katrien, additional, Finalet Ferreiro, Julio, additional, Tousseyn, Thomas, additional, Graux, Carlos, additional, Dierickx, Daan, additional, Vandenberghe, Peter, additional, and Cools, Jan, additional
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- 2014
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10. Abstract 4698: Gene expression profiling distinguishes between endometrial stromal tumors subtypes
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Przybyl, Joanna, primary, Kowalewska, Magdalena, additional, Quattrone, Anna, additional, Dewaele, Barbara, additional, Vanspauwen, Vanessa, additional, Finalet-Ferreiro, Julio, additional, Swierniak, Michal, additional, Bakula-Zalewska, Elwira, additional, Siedlecki, Janusz A., additional, Bidzinski, Mariusz, additional, Cools, Jan, additional, and Debiec-Rychter, Maria, additional
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- 2014
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11. Integrative Genomic and Transcriptomic Analysis Identified Candidate Genes Implicated in the Pathogenesis of Hepatosplenic T-Cell Lymphoma
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Finalet Ferreiro, Julio, primary, Rouhigharabaei, Leila, additional, Urbankova, Helena, additional, van der Krogt, Jo-Anne, additional, Michaux, Lucienne, additional, Shetty, Shashirekha, additional, Krenacs, Laszlo, additional, Tousseyn, Thomas, additional, De Paepe, Pascale, additional, Uyttebroeck, Anne, additional, Verhoef, Gregor, additional, Taghon, Tom, additional, Vandenberghe, Peter, additional, Cools, Jan, additional, and Wlodarska, Iwona, additional
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- 2014
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12. Non-IG Aberrations of FOXP1 in B-Cell Malignancies Lead to an Aberrant Expression of N-Truncated Isoforms of FOXP1
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Rouhigharabaei, Leila, primary, Finalet Ferreiro, Julio, additional, Tousseyn, Thomas, additional, van der Krogt, Jo-Anne, additional, Put, Natalie, additional, Haralambieva, Eugenia, additional, Graux, Carlos, additional, Maes, Brigitte, additional, Vicente, Carmen, additional, Vandenberghe, Peter, additional, Cools, Jan, additional, and Wlodarska, Iwona, additional
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- 2014
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13. Coactivated Platelet-Derived Growth Factor Receptor α and Epidermal Growth Factor Receptor Are Potential Therapeutic Targets in Intimal Sarcoma
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Dewaele, Barbara, primary, Floris, Giuseppe, additional, Finalet-Ferreiro, Julio, additional, Fletcher, Christopher D., additional, Coindre, Jean-Michel, additional, Guillou, Louis, additional, Hogendoorn, Pancras C.W., additional, Wozniak, Agnieszka, additional, Vanspauwen, Vanessa, additional, Schöffski, Patrick, additional, Marynen, Peter, additional, Vandenberghe, Peter, additional, Sciot, Raf, additional, and Debiec-Rychter, Maria, additional
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- 2010
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14. Pulmonary transcriptome analysis in the surgically induced rabbit model of diaphragmatic hernia treated with fetal tracheal occlusion
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Engels, Alexander C., Brady, Paul D., Kammoun, Molka, Finalet Ferreiro, Julio, DeKoninck, Philip, Endo, Masayuki, Toelen, Jaan, Vermeesch, Joris R., and Deprest, Jan
- Abstract
Congenital diaphragmatic hernia (CDH) is a malformation leading to pulmonary hypoplasia, which can be treated in utero by fetal tracheal occlusion (TO). However, the changes of gene expression induced by TO remain largely unknown but could be used to further improve the clinically used prenatal treatment of this devastating malformation. Therefore, we aimed to investigate the pulmonary transcriptome changes caused by surgical induction of diaphragmatic hernia (DH) and additional TO in the fetal rabbit model. Induction of DH was associated with 378 upregulated genes compared to controls when allowing a false-discovery rate (FDR) of 0.1 and a fold change (FC) of 2. Those genes were again downregulated by consecutive TO. But DH+TO was associated with an upregulation of 157 genes compared to DH and controls. When being compared to control lungs, 106 genes were downregulated in the DH group and were not changed by TO. Therefore, the overall pattern of gene expression in DH+TO is more similar to the control group than to the DH group. In this study, we further provide a database of gene expression changes induced by surgical creation of DH and consecutive TO in the rabbit model. Future treatment strategies could be developed using this dataset. We also discuss the most relevant genes that are involved in CDH.
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- 2016
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15. Non-IG Aberrations of FOXP1 in B-Cell Malignancies Lead to an Aberrant Expression of N-Truncated Isoforms of FOXP1.
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Rouhigharabaei, Leila, Finalet Ferreiro, Julio, Tousseyn, Thomas, van der Krogt, Jo-Anne, Put, Natalie, Haralambieva, Eugenia, Graux, Carlos, Maes, Brigitte, Vicente, Carmen, Vandenberghe, Peter, Cools, Jan, and Wlodarska, Iwona
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B cell lymphoma , *IMMUNOGLOBULINS , *OPTICAL aberrations , *CANCER genetics , *GENE expression , *NITROGEN , *TRANSCRIPTION factors , *LYMPHOMAS - Abstract
The transcription factor FOXP1 is implicated in the pathogenesis of B-cell lymphomas through chromosomal translocations involving either immunoglobulin heavy chain (IGH) locus or non-IG sequences. The former translocation, t(3;14)(p13;q32), results in dysregulated expression of FOXP1 juxtaposed with strong regulatory elements of IGH. Thus far, molecular consequences of rare non-IG aberrations of FOXP1 remain undetermined. Here, using molecular cytogenetics and molecular biology studies, we comprehensively analyzed four lymphoma cases with non-IG rearrangements of FOXP1 and compared these with cases harboring t(3;14)(p13;q32)/IGH-FOXP1 and FOXP1-expressing lymphomas with no apparent structural aberrations of the gene. Our study revealed that non-IG rearrangements of FOXP1 are usually acquired during clinical course of various lymphoma subtypes, including diffuse large B cell lymphoma, marginal zone lymphoma and chronic lymphocytic leukemia, and correlate with a poor prognosis. Importantly, these aberrations constantly target the coding region of FOXP1, promiscuously fusing with coding and non-coding gene sequences at various reciprocal breakpoints (2q36, 10q24 and 3q11). The non-IG rearrangements of FOXP1, however, do not generate functional chimeric genes but commonly disrupt the full-length FOXP1 transcript leading to an aberrant expression of N-truncated FOXP1 isoforms (FOXP1NT), as shown by QRT-PCR and Western blot analysis. In contrast, t(3;14)(p13;q32)/IGH-FOXP1 affects the 5′ untranslated region of FOXP1 and results in overexpress the full-length FOXP1 protein (FOXP1FL). RNA-sequencing of a few lymphoma cases expressing FOXP1NT and FOXP1FL detected neither FOXP1-related fusions nor FOXP1 mutations. Further bioinformatic analysis of RNA-sequencing data retrieved a set of genes, which may comprise direct or non-direct targets of FOXP1NT, potentially implicated in disease progression. In summary, our findings point to a dual mechanism through which FOXP1 is implicated in B-cell lymphomagenesis. We hypothesize that the primary t(3;14)(p13;q32)/IGH-FOXP1 activates expression of the FOXP1FL protein with potent oncogenic activity, whereas the secondary non-IG rearrangements of FOXP1 promote expression of the FOXP1NT proteins, likely driving progression of disease. [ABSTRACT FROM AUTHOR]
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- 2014
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16. Involvement of FERand FESin the Pathogenesis of Follicular Variant of Peripheral T-Cell Lymphoma
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Wlodarska, Iwona, van der Krogt, Jo-Anne, Van Roosbroeck, Katrien, Finalet Ferreiro, Julio, Tousseyn, Thomas, Graux, Carlos, Dierickx, Daan, Vandenberghe, Peter, and Cools, Jan
- Abstract
Peripheral T-cell lymphoma - not otherwise specified (PTCL-NOS) is the largest, most common and very heterogeneous category of PTCL. To date three PTCL variants have been described, including follicular variant (PTCL-F), a rare and poorly understood entity. Cytogenetically, PTCL-F is associated with a recurrent t(5;9)(q33;q22) resulting in the fusion of two protein tyrosine kinase (PTK) genes, ITKand SYK, showing constitutive activation of SYK.Transforming capacities of ITK-SYK were documented both in vitroand in vivo.Involvement of other PTK genes in the pathogenesis of PTCL-F has been postulated, but is thus far, not evidenced.
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- 2014
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17. t(X;14)(p11.4;q32.33) is recurrent in marginal zone lymphoma and up-regulates GPR34.
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Baens M, Finalet Ferreiro J, Tousseyn T, Urbankova H, Michaux L, de Leval L, Dierickx D, Wolter P, Sagaert X, Vandenberghe P, De Wolf-Peeters C, and Wlodarska I
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- Aged, Aged, 80 and over, Female, Humans, Lymphoma, B-Cell, Marginal Zone metabolism, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse metabolism, Male, Receptors, Lysophospholipid genetics, Up-Regulation, Chromosomes, Human, Pair 11 genetics, Chromosomes, Human, Pair 14 genetics, Lymphoma, B-Cell, Marginal Zone genetics, Receptors, Lysophospholipid metabolism
- Abstract
Genetic events underlying pathogenesis of nodal and extranodal marginal zone lymphoma are not completely understood. We report here a novel t(X;14)(p11.4;q32.33) identified in 4 lymphoma cases: 2 with a mucosa-associated lymphoid tissue lymphoma, one with a nodal marginal zone lymphoma and one with gastric diffuse large B-cell lymphoma. In all cases, lymphoma evolved from a previous auto-immune disorder. Fluorescence in situ hybridization and molecular studies showed that t(X;14), which is mediated by immunoglobulin heavy chain locus, targets the GPR34 gene at Xp11.4. Upregulation of GPR34 mRNA and aberrant expression of GPR34 protein has been demonstrated in 3 presented cases by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively. GPR34 belongs to the largest family of cell surface molecules involved in signal transmission that play important roles in many physiological and pathological processes, including tumorigenesis. Although functional consequences of t(X;14) have not been identified, our studies suggest that up-regulated GPR34 activate neither nuclear factor-κB nor ELK-related tyrosine kinase.
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- 2012
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18. Coactivated platelet-derived growth factor receptor {alpha} and epidermal growth factor receptor are potential therapeutic targets in intimal sarcoma.
- Author
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Dewaele B, Floris G, Finalet-Ferreiro J, Fletcher CD, Coindre JM, Guillou L, Hogendoorn PC, Wozniak A, Vanspauwen V, Schöffski P, Marynen P, Vandenberghe P, Sciot R, and Debiec-Rychter M
- Subjects
- Adult, Aged, Benzamides, Comparative Genomic Hybridization, Dasatinib, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, Female, Humans, Imatinib Mesylate, In Situ Hybridization, Fluorescence, Karyotyping, Male, Middle Aged, Phosphorylation, Piperazines pharmacology, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology, Receptor, Platelet-Derived Growth Factor alpha antagonists & inhibitors, Receptor, Platelet-Derived Growth Factor alpha genetics, Sarcoma drug therapy, Sarcoma genetics, Sarcoma pathology, Thiazoles pharmacology, Tunica Intima enzymology, Tunica Intima pathology, Vascular Neoplasms drug therapy, Vascular Neoplasms genetics, Vascular Neoplasms pathology, ErbB Receptors metabolism, Receptor, Platelet-Derived Growth Factor alpha metabolism, Sarcoma enzymology, Vascular Neoplasms enzymology
- Abstract
Intimal sarcoma (IS) is a rare, malignant, and aggressive tumor that shows a relentless course with a concomitant low survival rate and for which no effective treatment is available. In this study, 21 cases of large arterial blood vessel IS were analyzed by immunohistochemistry and fluorescence in situ hybridization and selectively by karyotyping, array comparative genomic hybridization, sequencing, phospho-kinase antibody arrays, and Western immunoblotting in search for novel diagnostic markers and potential molecular therapeutic targets. Ex vivo immunoassays were applied to test the sensitivity of IS primary tumor cells to the receptor tyrosine kinase (RTK) inhibitors imatinib and dasatinib. We showed that amplification of platelet-derived growth factor receptor α (PDGFRA) is a common finding in IS, which should be considered as a molecular hallmark of this entity. This amplification is consistently associated with PDGFRA activation. Furthermore, the tumors reveal persistent activation of the epidermal growth factor receptor (EGFR), concurrent to PDGFRA activation. Activated PDGFRA and EGFR frequently coexist with amplification and overexpression of the MDM2 oncogene. Ex vivo immunoassays on primary IS cells from one case showed the potency of dasatinib to inhibit PDGFRA and downstream signaling pathways. Our findings provide a rationale for investigating therapies that target PDGFRA, EGFR, or MDM2 in IS. Given the clonal heterogeneity of this tumor type and the potential cross-talk between the PDGFRA and EGFR signaling pathways, targeting multiple RTKs and aberrant downstream effectors might be required to improve the therapeutic outcome for patients with this disease., (©2010 AACR.)
- Published
- 2010
- Full Text
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