Search

Your search keyword '"Boi, Michela"' showing total 20 results
Start Over Author "Boi, Michela" Publication Year Range Last 10 years
20 results on '"Boi, Michela"'

2. Review on imidacloprid diffusion route and a case study: from apple orchard to the honey bee colony matrices.

Author

MALAGNINI, Valeria, FONTANA, Paolo, DI PRISCO, Gennaro, MEDRZYCKI, Piotr, ZANOTELLI, Livia, POWER, Karen, COLOMBO, Roberto, SERRA, Giorgia, BOI, Michela, and ANGELI, Gino

Abstract

Honey bees play a pivotal role in natural and rural ecosystems by providing human and animal food sources through pollination services. However, in cultivated areas, they can be exposed to the chemicals utilized for crop protection. Neonicotinoid insecticides can adversely affect honey bee colonies impairing their survival, immunity and biological activities at lethal and sublethal doses. For this reason, neonicotinoids, together with other stress factors, like pathogens (e.g. viruses and Varroa mites), climate change and food shortage, are considered one of the causes of worldwide colony losses. Nevertheless, the natural way of entry and diffusion of these pesticides in field colonies is not completely clear. Here, we wanted to fill this gap by studying the diffusion route of imidacloprid and its metabolites by analysing different matrices collected from honey bee colonies used for pollination of apple orchards, in the framework of applied Integrated Pest Management strategies. Pollen, honey bees, honey, royal jelly, bee wax and bee bread were sampled from 6 honey bee colonies placed in two different apple orchards before blooming, exposed to chemicals application and removed from the site after that. Samples were analysed using a liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS) in order to detect imidacloprid, olefin imidacloprid and 5-hydroxy imidacloprid. The results demonstrate that the primary way of entrance of imidacloprid was the pollen transported by foragers, while the main accumulation matrices were bee bread, honey and wax. These findings allow us to hypothesize that the accumulation of this insecticide, especially in bee bread, the main larval food, could potentially impact negatively on honey bee wellbeing at the adult stage. Moreover, our data could implement the honey bee colony simulator. [ABSTRACT FROM AUTHOR]

Published
2023

3. Supplemental Table S4 from The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs

Author

Boi, Michela, primary, Gaudio, Eugenio, primary, Bonetti, Paola, primary, Kwee, Ivo, primary, Bernasconi, Elena, primary, Tarantelli, Chiara, primary, Rinaldi, Andrea, primary, Testoni, Monica, primary, Cascione, Luciano, primary, Ponzoni, Maurilio, primary, Mensah, Afua Adjeiwaa, primary, Stathis, Anastasios, primary, Stussi, Georg, primary, Riveiro, María Eugenia, primary, Herait, Patrice, primary, Inghirami, Giorgio, primary, Cvitkovic, Esteban, primary, Zucca, Emanuele, primary, and Bertoni, Francesco, primary

Published
2023
Full Text
View/download PDF

4. Supplemental Figures S1-2 from The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs

Author

Boi, Michela, primary, Gaudio, Eugenio, primary, Bonetti, Paola, primary, Kwee, Ivo, primary, Bernasconi, Elena, primary, Tarantelli, Chiara, primary, Rinaldi, Andrea, primary, Testoni, Monica, primary, Cascione, Luciano, primary, Ponzoni, Maurilio, primary, Mensah, Afua Adjeiwaa, primary, Stathis, Anastasios, primary, Stussi, Georg, primary, Riveiro, María Eugenia, primary, Herait, Patrice, primary, Inghirami, Giorgio, primary, Cvitkovic, Esteban, primary, Zucca, Emanuele, primary, and Bertoni, Francesco, primary

Published
2023
Full Text
View/download PDF

5. Supplemental Figures S6 from The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs

Author

Boi, Michela, primary, Gaudio, Eugenio, primary, Bonetti, Paola, primary, Kwee, Ivo, primary, Bernasconi, Elena, primary, Tarantelli, Chiara, primary, Rinaldi, Andrea, primary, Testoni, Monica, primary, Cascione, Luciano, primary, Ponzoni, Maurilio, primary, Mensah, Afua Adjeiwaa, primary, Stathis, Anastasios, primary, Stussi, Georg, primary, Riveiro, María Eugenia, primary, Herait, Patrice, primary, Inghirami, Giorgio, primary, Cvitkovic, Esteban, primary, Zucca, Emanuele, primary, and Bertoni, Francesco, primary

Published
2023
Full Text
View/download PDF

6. Supplemental Table S2-3 from The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs

Author

Boi, Michela, primary, Gaudio, Eugenio, primary, Bonetti, Paola, primary, Kwee, Ivo, primary, Bernasconi, Elena, primary, Tarantelli, Chiara, primary, Rinaldi, Andrea, primary, Testoni, Monica, primary, Cascione, Luciano, primary, Ponzoni, Maurilio, primary, Mensah, Afua Adjeiwaa, primary, Stathis, Anastasios, primary, Stussi, Georg, primary, Riveiro, María Eugenia, primary, Herait, Patrice, primary, Inghirami, Giorgio, primary, Cvitkovic, Esteban, primary, Zucca, Emanuele, primary, and Bertoni, Francesco, primary

Published
2023
Full Text
View/download PDF

7. Supplemental Figures S3-5 from The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs

Author

Boi, Michela, primary, Gaudio, Eugenio, primary, Bonetti, Paola, primary, Kwee, Ivo, primary, Bernasconi, Elena, primary, Tarantelli, Chiara, primary, Rinaldi, Andrea, primary, Testoni, Monica, primary, Cascione, Luciano, primary, Ponzoni, Maurilio, primary, Mensah, Afua Adjeiwaa, primary, Stathis, Anastasios, primary, Stussi, Georg, primary, Riveiro, María Eugenia, primary, Herait, Patrice, primary, Inghirami, Giorgio, primary, Cvitkovic, Esteban, primary, Zucca, Emanuele, primary, and Bertoni, Francesco, primary

Published
2023
Full Text
View/download PDF

8. Convergent Mutations and Kinase Fusions Lead to Oncogenic STAT3 Activation in Anaplastic Large Cell Lymphoma

Author

Crescenzo, Ramona, Abate, Francesco, Lasorsa, Elena, Tabbo’, Fabrizio, Gaudiano, Marcello, Chiesa, Nicoletta, Di Giacomo, Filomena, Spaccarotella, Elisa, Barbarossa, Luigi, Ercole, Elisabetta, Todaro, Maria, Boi, Michela, Acquaviva, Andrea, Ficarra, Elisa, Novero, Domenico, Rinaldi, Andrea, Tousseyn, Thomas, Rosenwald, Andreas, Kenner, Lukas, Cerroni, Lorenzo, Tzankov, Alexander, Ponzoni, Maurilio, Paulli, Marco, Weisenburger, Dennis, Chan, Wing C., Iqbal, Javeed, Piris, Miguel A., Zamo’, Alberto, Ciardullo, Carmela, Rossi, Davide, Gaidano, Gianluca, Pileri, Stefano, Tiacci, Enrico, Falini, Brunangelo, Shultz, Leonard D., Mevellec, Laurence, Vialard, Jorge E., Piva, Roberto, Bertoni, Francesco, Rabadan, Raul, and Inghirami, Giorgio

Published
2015
Full Text
View/download PDF

10. Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts

Author

Scarfò, Irene, Pellegrino, Elisa, Mereu, Elisabetta, Kwee, Ivo, Agnelli, Luca, Bergaggio, Elisa, Garaffo, Giulia, Vitale, Nicoletta, Caputo, Manuel, Machiorlatti, Rodolfo, Circosta, Paola, Abate, Francesco, Barreca, Antonella, Novero, Domenico, Mathew, Susan, Rinaldi, Andrea, Tiacci, Enrico, Serra, Sara, Deaglio, Silvia, Neri, Antonino, Falini, Brunangelo, Rabadan, Raul, Bertoni, Francesco, Inghirami, Giorgio, Piva, Roberto, Boi, Michela, Crescenzo, Ramona, Cuccuru, Giuditta, Gaudiano, Marcello, Lasorsa, Elena, Medico, Enzo, Messana, Katia, Spaccarotella, Elisa, Tabbò, Fabrizio, Todaro, Maria, Fornari, Alessandro, Chilosi, Marco, Zamò, Alberto, Facchetti, Fabio, Lonardi, Silvia, De Chiara, Anna, Fulciniti, Franco, Doglioni, Claudio, Ponzoni, Maurilio, Todoerti, Katia, De Wolf Peeters, Christiane, Tousseyn, Thomas, Van Loo, Peter, Geissinger, Eva, Muller Hermelink, Hans Konrad, Rosenwald, Andreas, Matolcsy, Andras, Piris, Miguel Angel, Rodriguez Pinilla, Maria E., AGOSTINELLI, CLAUDIO, PICCALUGA, PIER PAOLO, PILERI, STEFANO, Scarfò, Irene, Pellegrino, Elisa, Mereu, Elisabetta, Kwee, Ivo, Agnelli, Luca, Bergaggio, Elisa, Garaffo, Giulia, Vitale, Nicoletta, Caputo, Manuel, Machiorlatti, Rodolfo, Circosta, Paola, Abate, Francesco, Barreca, Antonella, Novero, Domenico, Mathew, Susan, Rinaldi, Andrea, Tiacci, Enrico, Serra, Sara, Deaglio, Silvia, Neri, Antonino, Falini, Brunangelo, Rabadan, Raul, Bertoni, Francesco, Inghirami, Giorgio, Piva, Roberto, Boi, Michela, Crescenzo, Ramona, Cuccuru, Giuditta, Gaudiano, Marcello, Lasorsa, Elena, Medico, Enzo, Messana, Katia, Spaccarotella, Elisa, Tabbò, Fabrizio, Todaro, Maria, Fornari, Alessandro, Chilosi, Marco, Zamò, Alberto, Facchetti, Fabio, Lonardi, Silvia, De Chiara, Anna, Fulciniti, Franco, Doglioni, Claudio, Ponzoni, Maurilio, Todoerti, Katia, Agostinelli, Claudio, Piccaluga, Pier Paolo, Pileri, Stefano, De Wolf-Peeters, Christiane, Tousseyn, Thoma, Van Loo, Peter, Geissinger, Eva, Muller-Hermelink, Hans Konrad, Rosenwald, Andrea, Matolcsy, Andra, Piris, Miguel Angel, Rodriguez-Pinilla, Maria E., Scarfò, I, Pellegrino, E, Mereu, E, Kwee, I, Agnelli, L, Bergaggio, E, Garaffo, G, Vitale, N, Caputo, M, Machiorlatti, R, Circosta, P, Abate, F, Barreca, A, Novero, D, Mathew, S, Rinaldi, A, Tiacci, E, Serra, S, Deaglio, S, Neri, A, Falini, B, Rabadan, R, Bertoni, F, Inghirami, G, Piva, R, the European T-Cell Lymphoma Study, Group, Doglioni, C, and Ponzoni, M

Subjects
0301 basic medicine, Untranslated region, Receptor, ErbB-4, Messenger, Mice, SCID, Biochemistry, Mice, 0302 clinical medicine, 5' Untranslated Region, HEK293 Cell, Mutant Protein, Mice, Inbred NOD, hemic and lymphatic diseases, 5' Untranslated RegionsAnimalsCodon, Anaplastic lymphoma kinase, Anaplastic Lymphoma Kinase, NIH 3T3 Cell, Regulation of gene expression, TransgenicMolecular Sequence DataMutant ProteinsNIH 3T3 CellsReceptor Protein-Tyrosine KinasesReceptor, Hematology, Long terminal repeat, Large-Cell, Gene Expression Regulation, Neoplastic, Receptor Protein-Tyrosine Kinase, Codon, Nonsense, 030220 oncology & carcinogenesis, Lymphoma, Large-Cell, Anaplastic, Human, Molecular Sequence Data, Immunology, ErbB-4RNA, Mice, Transgenic, Biology, 03 medical and health sciences, Complementary DNA, Animals, Humans, RNA, Messenger, Gene, NonsenseGene Expression Regulation, NeoplasticHEK293 CellsHumansLymphoma, Animal, Receptor Protein-Tyrosine Kinases, RNA, Cell Biology, Molecular biology, Gene expression profiling, HEK293 Cells, 030104 developmental biology, Inbred NODMice, NIH 3T3 Cells, Mutant Proteins, SCIDMice, AnaplasticMiceMice, 5' Untranslated Regions, 5' Untranslated RegionsAnimalsCodon, NonsenseGene Expression Regulation, NeoplasticHEK293 CellsHumansLymphoma, Large-Cell, AnaplasticMiceMice, Inbred NODMice, SCIDMice, TransgenicMolecular Sequence DataMutant ProteinsNIH 3T3 CellsReceptor Protein-Tyrosine KinasesReceptor, ErbB-4RNA, Messenger
Abstract

Anaplastic large-cell lymphoma (ALCL) is a clinical and biological heterogeneous disease that includes systemic anaplastic lymphoma kinase (ALK)-positive and ALK-negative entities. To discover biomarkers and/or genes involved in ALK-negative ALCL pathogenesis, we applied the cancer outlier profile analysis algorithm to a gene expression profiling data set including 249 cases of T-cell non-Hodgkin lymphoma and normal T cells. Ectopic coexpression of ERBB4 and COL29A1 genes was detected in 24% of ALK-negative ALCL patients. RNA sequencing and 5' RNA ligase-mediated rapid amplification of complementary DNA ends identified 2 novel ERBB4-truncated transcripts displaying intronic transcription start sites. By luciferase assays, we defined that the expression of ERBB4-aberrant transcripts is promoted by endogenous intronic long terminal repeats. ERBB4 expression was confirmed at the protein level by western blot analysis and immunohistochemistry. Lastly, we demonstrated that ERBB4-truncated forms show oncogenic potentials and that ERBB4 pharmacologic inhibition partially controls ALCL cell growth and disease progression in an ERBB4-positive patient-derived tumorgraft model. In conclusion, we identified a new subclass of ALK-negative ALCL characterized by aberrant expression of ERBB4-truncated transcripts carrying intronic 5' untranslated regions. © 2016 by The American Society of Hematology.

Published
2016
Full Text
View/download PDF

14. Epigenomic evolution in diffuse large B-cell lymphomas

Author

Pan, Heng, primary, Jiang, Yanwen, additional, Boi, Michela, additional, Tabbò, Fabrizio, additional, Redmond, David, additional, Nie, Kui, additional, Ladetto, Marco, additional, Chiappella, Annalisa, additional, Cerchietti, Leandro, additional, Shaknovich, Rita, additional, Melnick, Ari M., additional, Inghirami, Giorgio G., additional, Tam, Wayne, additional, and Elemento, Olivier, additional

Published
2015
Full Text
View/download PDF

15. The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs

Author

Boi, Michela, primary, Gaudio, Eugenio, additional, Bonetti, Paola, additional, Kwee, Ivo, additional, Bernasconi, Elena, additional, Tarantelli, Chiara, additional, Rinaldi, Andrea, additional, Testoni, Monica, additional, Cascione, Luciano, additional, Ponzoni, Maurilio, additional, Mensah, Afua Adjeiwaa, additional, Stathis, Anastasios, additional, Stussi, Georg, additional, Riveiro, María Eugenia, additional, Herait, Patrice, additional, Inghirami, Giorgio, additional, Cvitkovic, Esteban, additional, Zucca, Emanuele, additional, and Bertoni, Francesco, additional

Published
2015
Full Text
View/download PDF

16. A 10 year survey of acaricide residues in beeswax analysed in Italy.

Author

Boi, Michela, Serra, Giorgia, Colombo, Roberto, Lodesani, Marco, Massi, Sergio, and Costa, Cecilia

Subjects
ACARICIDES, BEESWAX, INSECTICIDE residues, BEEKEEPING, GAS chromatography, VARROA destructor, HONEYBEES
Abstract

BACKGROUND The aim of this work was to provide an overview of the prevalence and level of acaricides in beeswax used in Italy in the past 10 years by analysing 1319 beeswax samples processed by the certified laboratory of the Italian Bee Research Institute. RESULTS The proportion of samples positive to at least one active ingredient decreased between 2005 and 2009 (from 69 to 32%) and then increased again between 2009 and 2014 (from 32 to 91%). This trend is in agreement with reports from beekeepers that the use of synthetic acaricides decreased in the second half of the past decade and increased after the beginning of the colony losses phenomenon. The active ingredient with the greatest overall proportion of positive samples was coumaphos (49%), followed by fluvalinate (38%) and chlorphenvinphos (25%). The indicator for amitraz, 2,4-dimethylphenylformamide ( DMPF), was detected in a very small proportion of samples (6%), while residues of cymiazole were never found. CONCLUSIONS In more than half of the analysed samples, residues of at least one active ingredient were detected. The mean levels of residues of all the considered active ingredients in the positive samples may represent a source of accumulation in beeswax and pose risks to honey bee health. © 2015 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Published
2016
Full Text
View/download PDF

17. PRDM1/BLIMP1: a tumor suppressor gene in B and T cell lymphomas.

Author

Boi, Michela, Zucca, Emanuele, Inghirami, Giorgio, and Bertoni, Francesco

Subjects
*TUMOR suppressor genes, *T cells, *B cells, *LYMPHOID tissue, *CELL differentiation, *KILLER cells
Abstract

The gene encoding the human BLIMP1, prdm1, is located on chromosome 6q21, a locus frequently deleted in lymphoid tumors. BLIMP1 is able to silence its target genes in a context-dependent manner through different mechanisms. BLIMP1 is expressed in both B and T cells, in which it plays important functions. In B cells, BLIMP1 acts as the master regulator of plasma cell differentiation, repressed by BCL6 and repressing both BCL6 and PAX5. In T cells, BLIMP1 is a critical factor for most terminal effector cell differentiation in both CD4+ and CD8+ T cells. BLIMP1 is frequently inactivated in a variety of lymphomas, including diffuse large B cell lymphomas, Natural Killer cell lymphoma and anaplastic large T cell lymphoma. In this review, we will summarize the role of BLIMP1 in normal cells, focusing on lymphoid cells, and on its function as tumor suppressor gene in lymphomas. [ABSTRACT FROM AUTHOR]

Published
2015
Full Text
View/download PDF

18. The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs

Author

Emanuele Zucca, Maurilio Ponzoni, Georg Stussi, Andrea Rinaldi, Eugenio Gaudio, Maria E. Riveiro, Ivo Kwee, Afua Adjeiwaa Mensah, Giorgio Inghirami, Luciano Cascione, Paola Bonetti, Monica Testoni, Esteban Cvitkovic, Patrice Herait, Francesco Bertoni, Chiara Tarantelli, Elena Bernasconi, Michela Boi, Anastasios Stathis, Boi, Michela, Gaudio, Eugenio, Bonetti, Paola, Kwee, Ivo, Bernasconi, Elena, Tarantelli, Chiara, Rinaldi, Andrea, Testoni, Monica, Cascione, Luciano, Ponzoni, Maurilio, Mensah, Afua Adjeiwaa, Stathis, Anastasio, Stussi, Georg, Riveiro, María Eugenia, Herait, Patrice, Inghirami, Giorgio, Cvitkovic, Esteban, Zucca, Emanuele, and Bertoni, Francesco

Subjects
Cancer Research, Chromatin Immunoprecipitation, Lymphoma, B-Cell, Blotting, Western, Antineoplastic Agents, Apoptosis, Mice, SCID, Biology, Real-Time Polymerase Chain Reaction, Mice, In vivo, Mice, Inbred NOD, Cell Line, Tumor, medicine, Animals, Humans, Epigenetics, PI3K/AKT/mTOR pathway, B cell, Cell Proliferation, Cancer, Nuclear Proteins, Drug Synergism, Epigenome, medicine.disease, Immunohistochemistry, Xenograft Model Antitumor Assays, Bromodomain, medicine.anatomical_structure, Oncology, Immunology, Cancer cell, Cancer research, Acetanilides, Transcriptome, Heterocyclic Compounds, 3-Ring
Abstract

Purpose: In cancer cells, the epigenome is often deregulated, and inhibition of the bromodomain and extra-terminal (BET) family of bromodomain-containing proteins is a novel epigenetic therapeutic approach. Preliminary results of an ongoing phase I trial have reported promising activity and tolerability with the new BET bromodomain inhibitor OTX015. Experimental Design: We assessed the preclinical activity of OTX015 as single agent and in combination in mature B-cell lymphoma models and performed in vitro and in vivo experiments to identify the mechanism of action and the genetic features associated with sensitivity to the compound. Results: OTX015 showed antiproliferative activity in a large panel of cell lines derived from mature B-cell lymphoid tumors with median IC50 of 240 nmol/L, without significant differences among the different histotypes. In vitro and in vivo experiments showed that OTX015 targeted NFKB/TLR/JAK/STAT signaling pathways, MYC- and E2F1-regulated genes, cell-cycle regulation, and chromatin structure. OTX015 presented in vitro synergism with several anticancer agents, especially with mTOR and BTK inhibitors. Gene expression signatures associated with different degrees of sensitivity to OTX015 were identified. Although OTX015 was mostly cytostatic, the compound induced apoptosis in a genetically defined subgroup of cells, derived from activated B-cell–like diffuse large B-cell lymphoma, bearing wtTP53, mutations in MYD88, and CD79B or CARD11. Conclusions: Together with the data coming from the ongoing phase I study, the in vitro and in vivo data presented here provide the basis for further clinical investigation of OTX015 as single agent and in combination therapies. Clin Cancer Res; 21(7); 1628–38. ©2015 AACR.

Published
2015

19. Convergent Mutations and Kinase Fusions Lead to Oncogenic STAT3 Activation in Anaplastic Large Cell Lymphoma

Author

Lorenzo Cerroni, Laurence Mevellec, Andreas Rosenwald, Giorgio Inghirami, Luigi Barbarossa, Elena Lasorsa, Enrico Tiacci, Miguel A. Piris, Francesco Bertoni, Davide Rossi, Elisabetta Ercole, Nicoletta Chiesa, Filomena Di Giacomo, Domenico Novero, Maria Todaro, Alberto Zamò, Jorge Vialard, Ramona Crescenzo, Alexander Tzankov, Andrea Rinaldi, Lukas Kenner, Leonard D. Shultz, Francesco Abate, Thomas Tousseyn, Raul Rabadan, Javeed Iqbal, Dennis D. Weisenburger, Brunangelo Falini, Carmela Ciardullo, Elisa Ficarra, Wing C. Chan, Gianluca Gaidano, Elisa Spaccarotella, Andrea Acquaviva, Roberto Piva, Stefano Pileri, Fabrizio Tabbò, Marcello Gaudiano, Michela Boi, Marco Paulli, Maurilio Ponzoni, Crescenzo, Ramona, Abate, Francesco, Lasorsa, Elena, Tabbo', Fabrizio, Gaudiano, Marcello, Chiesa, Nicoletta, Di Giacomo, Filomena, Spaccarotella, Elisa, Barbarossa, Luigi, Ercole, Elisabetta, Todaro, Maria, Boi, Michela, Acquaviva, Andrea, Ficarra, Elisa, Novero, Domenico, Rinaldi, Andrea, Tousseyn, Thoma, Rosenwald, Andrea, Kenner, Luka, Cerroni, Lorenzo, Tzankov, Alexander, Ponzoni, Maurilio, Paulli, Marco, Weisenburger, Denni, Chan, Wing C, Iqbal, Javeed, Piris, Miguel A, Zamo', Alberto, Ciardullo, Carmela, Rossi, Davide, Gaidano, Gianluca, Pileri, Stefano, Tiacci, Enrico, Falini, Brunangelo, Shultz, Leonard D, Mevellec, Laurence, Vialard, Jorge E, Piva, Roberto, Bertoni, Francesco, Rabadan, Raul, Inghirami, Giorgio, Ramona Crescenzo, Francesco Abate, Elena Lasorsa, Fabrizio Tabbo’, Marcello Gaudiano, Nicoletta Chiesa, Filomena Di Giacomo, Elisa Spaccarotella, Luigi Barbarossa, Elisabetta Ercole, Maria Todaro, Michela Boi, ACQUAVIVA, ANDREA, FICARRA, ELISA, Domenico Novero, Andrea Rinaldi, Thomas Tousseyn, Andreas Rosenwald, Lukas Kenner, Lorenzo Cerroni, Alexander Tzankov, Maurilio Ponzoni, Marco Paulli, Dennis Weisenburger, Wing C. Chan, Javeed Iqbal, Miguel A. Piri, Alberto Zamo’, Carmela Ciardullo, Davide Rossi, Gianluca Gaidano, Stefano Pileri, Enrico Tiacci, Brunangelo Falini, Leonard D. Shultz, Laurence Mevellec, Jorge E. Vialard, Roberto Piva, Francesco Bertoni, Raul Rabadan, and Giorgio Inghirami

Subjects
Cancer Research, Lymphoma, Somatic cell, massive sequencing, Activating Transcription Factor 3, Animals, Cell Line, Tumor, HEK293 Cells, Humans, Janus Kinase 1, Lymphoma, Large-Cell, Anaplastic, Mice, Mutant Chimeric Proteins, NF-kappa B, Phosphorylation, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, STAT3 Transcription Factor, Signal Transduction, TYK2 Kinase, Gene Expression Regulation, Neoplastic, Cell Biology, Oncology, Medicine (all), Anaplastic Large Cell Lymphoma, JAK/STAT3 pathway, Oncogenic STAT3 Activation, gene fusions, 0302 clinical medicine, hemic and lymphatic diseases, RNA-Seq data, anaplastic large cell lymphoma (ALCL), driver genetic alterations, somatic point mutations, copy number alterations, Anaplastic, Anaplastic lymphoma kinase, Anaplastic large-cell lymphoma, 0303 health sciences, Tumor, Janus kinase 1, Kinase, Large-Cell, 3. Good health, driver genetic alteration, somatic point mutation, Tyrosine kinase 2, 030220 oncology & carcinogenesis, Tyrosine kinase, Biology, Article, Cell Line, 03 medical and health sciences, ROS1, medicine, 030304 developmental biology, Stat3 activation, Neoplastic, Point mutation, gene fusion, medicine.disease, Molecular biology, Gene Expression Regulation, Cancer cell, Cancer research
Abstract

JAK/STAT3 signaling pathway is often deregulated in hematopoietic disorders including peripheral T-cell lymphoma. We describe two novel mechanisms leading to the constitutive activation of STAT3 in ALK- ALCL. Oncogenic JAK1 or STAT3 mutations are associated to hyperactive pSTAT3 that regulated canonical STAT3 and ATF3 genes. Moreover, synergizing JAK1 and STAT3 mutants sustain the neoplastic growth, which can be efficiently controlled in vitro and in an ALCL patient derived tumorgraft model by JAK1/2 inhibitors. We have discovered that novel chimera, displaying concomitant transcriptional and kinase activities, are power oncogenes capable to sustain via STAT3 the ALCL phenotype and can be uniquely neutralized by a novel ROS1 inhibitor. The pharmacological inhibition of JAK/STAT3 represents a novel strategy for the treatment of molecular stratified ALCL.

Published
2015

20. Therapeutic efficacy of the bromodomain inhibitor OTX015/MK-8628 in ALK-positive anaplastic large cell lymphoma: an alternative modality to overcome resistant phenotypes.

Author

Boi M, Todaro M, Vurchio V, Yang SN, Moon J, Kwee I, Rinaldi A, Pan H, Crescenzo R, Cheng M, Cerchietti L, Elemento O, Riveiro ME, Cvitkovic E, Bertoni F, and Inghirami G

Subjects
Anaplastic Lymphoma Kinase, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Synergism, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Humans, Inhibitory Concentration 50, Lymphoma, Large-Cell, Anaplastic genetics, Lymphoma, Large-Cell, Anaplastic pathology, Phenotype, Signal Transduction drug effects, Time Factors, Transcriptome, Acetanilides pharmacology, Antineoplastic Agents pharmacology, Biomarkers, Tumor genetics, Drug Resistance, Neoplasm drug effects, Heterocyclic Compounds, 3-Ring pharmacology, Lymphoma, Large-Cell, Anaplastic drug therapy, Receptor Protein-Tyrosine Kinases genetics
Abstract

Anaplastic large cell lymphomas (ALCL) represent a peripheral T-cell lymphoma subgroup, stratified based on the presence or absence of anaplastic lymphoma kinase (ALK) chimeras. Although ALK-positive ALCLs have a more favorable outcome than ALK-negative ALCL, refractory and/or relapsed forms are common and novel treatments are needed. Here we investigated the therapeutic potential of a novel bromodomain inhibitor, OTX015/MK-8628 in ALK-positive ALCLs.The effects of OTX015 on a panel of ALK+ ALCL cell lines was evaluated in terms of proliferation, cell cycle and downstream signaling, including gene expression profiling analyses. Synergy was tested with combination targeted therapies.Bromodomain inhibition with OTX015 led primarily to ALCL cell cycle arrest in a dose-dependent manner, along with downregulation of MYC and its downstream regulated genes. MYC overexpression did not compensate this OTX015-mediated phenotype. Transcriptomic analysis of OTX015-treated ALCL cells identified a gene signature common to various hematologic malignancies treated with bromodomain inhibitors, notably large cell lymphoma. OTX015-modulated genes included transcription factors (E2F2, NFKBIZ, FOS, JUNB, ID1, HOXA5 and HOXC6), members of multiple signaling pathways (ITK, PRKCH, and MKNK2), and histones (clusters 1-3). Combination of OTX015 with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib led to cell cycle arrest then cell death, and combination with suboptimal doses of the ALK inhibitor CEP28122 caused cell cycle arrest. When OTX015 was associated with GANT61, a selective GLI1/2 inhibitor, C1156Y-resistant ALK ALCL growth was impaired.These findings support OTX015 clinical trials in refractory ALCL in combination with inhibitors of interleukin-2-inducible kinase or SHH/GLI1.

Published
2016
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results