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1. Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK+ anaplastic large cell lymphoma

Author

Karaca Atabay, Elif, Mecca, Carmen, Wang, Qi, Ambrogio, Chiara, Mota, Ines, Prokoph, Nina, Mura, Giulia, Martinengo, Cinzia, Patrucco, Enrico, Leonardi, Giulia, Hossa, Jessica, Pich, Achille, Mologni, Luca, Gambacorti-Passerini, Carlo, Brugières, Laurence, Geoerger, Birgit, Turner, Suzanne D., Voena, Claudia, Cheong, Taek-Chin, and Chiarle, Roberto

Published
2022
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2. Wiskott–Aldrich syndrome protein (WASP) is a tumor suppressor in T cell lymphoma

Author

Menotti, Matteo, Ambrogio, Chiara, Cheong, Taek-Chin, Pighi, Chiara, Mota, Ines, Cassel, Seth H., Compagno, Mara, Wang, Qi, Dall’Olio, Riccardo, Minero, Valerio G., Poggio, Teresa, Sharma, Geeta Geeta, Patrucco, Enrico, Mastini, Cristina, Choudhari, Ramesh, Pich, Achille, Zamo, Alberto, Piva, Roberto, Giliani, Silvia, Mologni, Luca, Collings, Clayton K., Kadoch, Cigall, Gambacorti-Passerini, Carlo, Notarangelo, Luigi D., Anton, Ines M., Voena, Claudia, and Chiarle, Roberto

Published
2019
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3. The Dilemma of HER2 Double-equivocal Breast Carcinomas: Genomic Profiling and Implications for Treatment

Author

Marchiò, Caterina, Dell’Orto, Patrizia, Annaratone, Laura, Geyer, Felipe C., Venesio, Tiziana, Berrino, Enrico, Verdun di Cantogno, Ludovica, Garofoli, Andrea, Rangel, Nelson, Casorzo, Laura, dell’Aglio, Carmine, Gugliotta, Patrizia, Trisolini, Elena, Beano, Alessandra, Pietribiasi, Francesca, Orlassino, Renzo, Cassoni, Paola, Pich, Achille, Montemurro, Filippo, Mottolese, Marcella, Vincent-Salomon, Anne, Penault-Llorca, Frédérique, Medico, Enzo, Ng, Charlotte K.Y., Viale, Giuseppe, and Sapino, Anna

Published
2018
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14. JAK2V617F, CALR, and MPL Mutations and Bone Marrow Histology in Patients with Essential Thrombocythaemia

Author

Pich, Achille, Riera, Ludovica, Francia di Celle, Paola, Beggiato, Eloise, Benevolo, Giulia, and Godio, Laura

Subjects
Adult, Aged, 80 and over, Male, MPL mutation, DNA Mutational Analysis, CALR mutation, Janus Kinase 2, Middle Aged, Bone marrow biopsy, Essential thrombocythaemia, JAK2V617F mutation, Bone Marrow, Mutation, Humans, Female, Calreticulin, Receptors, Thrombopoietin, Aged, Thrombocythemia, Essential
Abstract

Mutations in the JAK2, CALR, and MPL genes have been shown to have prognostic value in essential thrombocythaemia (ET), but no clear association with morphological changes has been reported so far. We investigated the possible correlation between gene mutations and histopathological features in bone marrow (BM) biopsies of patients with ET.Marrow cellularity, fibrosis, and the number of total and dysmorphic megakaryocytes and clusters of megakaryocytes were compared to gene mutations in 90 cases of ET at diagnosis.The JAK2V617F mutation was found in 58.9%, CALR in 28.9%, and MPL in 4.4% of the cases, and 7.8% were triple-negative. JAK2V617F-mutated ET showed a high BM cellularity, the lowest number of clusters of megakaryocytes and the highest number of dysmorphic megakaryocytes; CALR-mutated ET showed a reduced BM cellularity, many clusters of large megakaryocytes, and very few dysmorphic megakaryocytes; MPL-mutated ET showed the lowest BM cellularity, the highest number of clustered and large megakaryocytes, and the lowest number of dysmorphic megakaryocytes. Triple-negative ET cases had the highest BM cellularity.Distinct morphological patterns were associated with gene mutations in ET, supporting the classification of ET into different subtypes.

Published
2018

16. Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK+anaplastic large cell lymphoma

Author

Karaca Atabay, Elif, Mecca, Carmen, Wang, Qi, Ambrogio, Chiara, Mota, Ines, Prokoph, Nina, Mura, Giulia, Martinengo, Cinzia, Patrucco, Enrico, Leonardi, Giulia, Hossa, Jessica, Pich, Achille, Mologni, Luca, Gambacorti-Passerini, Carlo, Brugières, Laurence, Geoerger, Birgit, Turner, Suzanne D., Voena, Claudia, Cheong, Taek-Chin, and Chiarle, Roberto

Abstract

Anaplastic large cell lymphomas (ALCLs) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. Targeting ALK using tyrosine kinase inhibitors (TKIs) is a therapeutic option in cases relapsed after chemotherapy, but TKI resistance may develop. By applying genomic loss-of-function screens, we identified PTPN1 and PTPN2 phosphatases as consistent top hits driving resistance to ALK TKIs in ALK+ALCL. Loss of either PTPN1 or PTPN2 induced resistance to ALK TKIs in vitro and in vivo. Mechanistically, we demonstrated that PTPN1 and PTPN2 are phosphatases that bind to and regulate ALK phosphorylation and activity. In turn, oncogenic ALK and STAT3 repress PTPN1 transcription. We found that PTPN1 is also a phosphatase for SHP2, a key mediator of oncogenic ALK signaling. Downstream signaling analysis showed that deletion of PTPN1 or PTPN2 induces resistance to crizotinib by hyperactivating SHP2, the MAPK, and JAK/STAT pathways. RNA sequencing of patient samples that developed resistance to ALK TKIs showed downregulation of PTPN1 and PTPN2 associated with upregulation of SHP2 expression. Combination of crizotinib with a SHP2 inhibitor synergistically inhibited the growth of wild-type or PTPN1/PTPN2 knock-out ALCL, where it reverted TKI resistance. Thus, we identified PTPN1 and PTPN2 as ALK phosphatases that control sensitivity to ALK TKIs in ALCL and demonstrated that a combined blockade of SHP2 potentiates the efficacy of ALK inhibition in TKI-sensitive and -resistant ALK+ALCL.

Published
2022
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18. Argyrophilic nucleolar organizer region counts predict survival in thymoma

Author

Pich, Achille, Chiarle, Roberto, Chiusa, Luigi, and Palestro, Giorgio

Subjects
Nucleolus organizer region -- Physiological aspects, Thymoma -- Prognosis, Cancer invasiveness -- Physiological aspects, Health
Abstract

Background. The prognosis of thymoma is related mainly to the tumor stage. The prognostic value of argyrophilic nucleolar organizer regions (AgNORs) has been demonstrated in several human neoplasias. Ninety primary thymomas were investigated retrospectively to assess whether AgNOR analysis could offer additional prognostic information. Methods. Sections from surgically resected thymomas, routinely fixed in formol and embedded in paraffin, were stained with the argyrophilic method of Ploton. The mean number of AgNORs in the nuclei of 100 tumor cells (AgNOR counts) was calculated for each case. The association between AgNOR counts and survival was assessed by means of uni- and multivariate survival analyses. Results. On univariate analysis, AgNOR counts were associated significantly with 5- and 10-year survival rates (95% and 96%, respectively, for thymomas with 5.58 or fewer AgNORs per cell, but only 55% and 44%, respectively, for tumors with more than 5.58 AgNORs per celll; P < 0.0001). Histologic subtypes of the American classification (P = 0.0006) and clinical stage (P < 0.0001) also were correlated with prognosis. The multivariate survival analysis showed that AgNOR counts (P < 0.001), clinical stage (P < 0.001), and age (P = 0.011) were independent prognostic variables. AgNOR counts were associated with histologic subtypes in the American (P = 0.0001) and European (P < 0.005) classifications and with the clinical stage (P < 0.0001). Moreover, thymoma cells and intermingling lymphocytes showed different numbers of AgNORs and patterns of AgNOR distribution. Conclusions. Analysis of argyrophilic nucleolar organizer regions provides useful prognostic information for patients with thymomas and offers an exact evaluation of the proliferative activity of the neoplastic cells even for thymomas with prominent lymphocytic infiltration.

Published
1994

20. Wiskott–Aldrich syndrome protein (WASP) is a tumor suppressor in T cell lymphoma

Author

Menotti, Matteo, primary, Ambrogio, Chiara, additional, Cheong, Taek-Chin, additional, Pighi, Chiara, additional, Mota, Ines, additional, Cassel, Seth H., additional, Compagno, Mara, additional, Wang, Qi, additional, Dall’Olio, Riccardo, additional, Minero, Valerio G., additional, Poggio, Teresa, additional, Sharma, Geeta Geeta, additional, Patrucco, Enrico, additional, Mastini, Cristina, additional, Choudhari, Ramesh, additional, Pich, Achille, additional, Zamo, Alberto, additional, Piva, Roberto, additional, Giliani, Silvia, additional, Mologni, Luca, additional, Collings, Clayton K., additional, Kadoch, Cigall, additional, Gambacorti-Passerini, Carlo, additional, Notarangelo, Luigi D., additional, Anton, Ines M., additional, Voena, Claudia, additional, and Chiarle, Roberto, additional

Published
2018
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22. Beyond NPM-anaplastic lymphoma kinase driven lymphomagenesis

Author

Fabrizio Tabbò, Maurilio Ponzoni, Raul Rabadan, Francesco Bertoni, Giorgio Inghirami European T. cell Lymphoma Study Group, Aliberti Sabrina, Barreca Antonella, Besson Luca, Crescenzo Ramona, Di Giacomo Filomena, Gaudiano Marcello, Inghirami Giorgio, Landra Indira, Lasorsa Elena, Machiorlatti Rodolfo, Mereu Elisabetta, Messana Katia, Novero Domenico, Pellegrino Elisa, Pich Achille, Piva Roberto, Scarfo Irene, Spaccarotella Elisa, Tabbo Fabrizio, Todaro Maria, Ubezzi Ivana, Urigu Susanna, Vittone Francesco, Abage Francesco, Ficarra Elisa, Acquaviva Andrea, Ponzoni Maurilio, Stella Carmelo, AGOSTINELLI, CLAUDIO, PICCALUGA, PIER PAOLO, PILERI, STEFANO, Falini Brunangelo, Tiacci Enrico, Bertoni Francesco, Boi Michela, Kwee Ivo, Fabrizio Tabbò,Maurilio Ponzoni,Raul Rabadan,Francesco Bertoni,Giorgio Inghirami European T-cell Lymphoma Study Group, Aliberti Sabrina, Barreca Antonella, Besson Luca, Crescenzo Ramona, Di Giacomo Filomena, Gaudiano Marcello, Inghirami Giorgio, Landra Indira, Lasorsa Elena, Machiorlatti Rodolfo, Mereu Elisabetta, Messana Katia, Novero Domenico, Pellegrino Elisa, Pich Achille, Piva Roberto, Scarfo Irene, Spaccarotella Elisa, Tabbo Fabrizio, Todaro Maria, Ubezzi Ivana, Urigu Susanna, Vittone Francesco, Abage Francesco, Ficarra Elisa, Acquaviva Andrea, Ponzoni Maurilio, Stella Carmelo, Agostinelli Claudio, Piccaluga Pier Paolo, Pileri Stefano, Falini Brunangelo, Tiacci Enrico, Bertoni Francesco, Boi Michela, and Kwee Ivo

Subjects
Anaplastic lymphoma kinase, Kinase inhibitor, Signalling pathways, hemic and lymphatic diseases, Lymphoid differentiation, Mouse model
Abstract

PURPOSE OF REVIEW: Anaplastic large cell lymphomas (ALCLs) are rare entities whose somatic genetic lesions have been identified only in a subset of patients. Thus, an integrated and massive discovery programme is required to define their tumourigenic alterations and to design more successful tailored therapies. RECENT FINDINGS: The discovery of anaplastic lymphoma kinase (ALK) fusions has provided the basis for the characterization of distinct subsets among ALCL patients. Although the oncogenic addiction of ALK signalling is proven, the tumorigenic contribution of coactivating lesions is still missing. As ALK- and ALK+ share common signatures, it is plausible that analogous mechanisms of transformation may be operating in both subsets, as confirmed by the dysregulated activation of c-MYC, RAS and NFκB, and the loss of Blimp-1 and p53/p63 axis. Nonetheless, recurrent genetic alterations for ALK- ALCL or refractory leukaemic ALK+ ALCL are lacking. Moreover, although conventional chemotherapies (anthracycline-based) are most successful, that is in ALK+ ALCL patients, the implementation of ALK inhibitors or of anti-CD30 based treatments provides innovative solutions, particularly in paediatric ALK+ ALCL and in chemorefractory/relapsed patients. SUMMARY: The complete portrayal of the landscape of genetic alterations in ALCL will dictate the development of innovative chemotherapeutic and targeted therapies that will fit most with the molecular and clinical profiling of individual patients.

Published
2013

23. Essential Differences in Clinical and Bone Marrow Features in BCR/ABL-Positive Thrombocythemia Compared to Thrombocythemia in the BCR/ABL-Negative Myeloproliferative Neoplasms Essential Thrombocythemia and Polycythemia Vera

Author

Michiels, Jj, Pich, Achille, De Raeve, H, Gadisseur, A., and Basic (bio-) Medical Sciences

Subjects
Male, Essential Trombocythemia, BCR-ABL Positive, Biopsy, Fusion Proteins, bcr-abl, Piperazines, Diagnosis, Differential, Bone Marrow, Humans, Hydroxyurea, Polycythemia Vera, Alleles, Aged, Myeloproliferative Disorders, Platelet Count, Janus Kinase 2, Middle Aged, Pyrimidines, Treatment Outcome, Benzamides, Mutation, Imatinib Mesylate, Quinazolines, Drug Therapy, Combination, Female, Human medicine, Thrombocythemia, Essential
Published
2015

24. Thymic epithelial tumors express vascular endothelial growth factors and their receptors as potential targets of antiangiogenic therapy: A tissue micro array-based multicenter study

Author

Lattanzio, R, La Sorda, R, Facciolo, F, Sioletic, S, Lauriola, L, Martucci, R, Gallo, E, Palmieri, G, Evoli, A, Alessandrini, G, Ruco, L, Rendina, Ea, Truini, M, Chiarle, Roberto, Barreca, A, Pich, Achille, Ascani, S, Remotti, D, Tunesi, G, Granone, P, Ratto, Gb, Puma, F, Pescarmona, E, Piantelli, M, Marino, M, Carlini, S, Cerasoli, V, Corzani, F, Melis, E, Filippetti, M, Canalini, P, Palestro, G, Lalle, M, Ruffini, Enrico, Ceribelli, A, Rinaldi, Mauro, and Thymic Epithelial Tumor Working Group

Subjects
Male, Vascular Endothelial Growth Factor A, Cancer Research, Pathology, Angiogenesis, Angiogenesis Inhibitors, Receptor tyrosine kinase, ANGIOGENESIS, chemistry.chemical_compound, 0302 clinical medicine, Thymoma, Thymic epithelial tumors, Biomarkers, Tissue Micro Array, Vascular endothelial growth factor, Vascular endothelial growth factor receptor, Medicine, Molecular Targeted Therapy, Neoplasms, Glandular and Epithelial, Child, Aged, 80 and over, 0303 health sciences, HISTOLOGIC CLASSIFICATION, MALIGNANT THYMOMA, BREAST-CANCER, CARCINOMAS, VEGF, INHIBITOR, OVEREXPRESSION, TOMOGRAPHY, CHALLENGES, biology, Neovascularization, Pathologic, tissue micro array, thymic epithelial tumors, vascular endothelial growth factor, biomarkers, thymoma, vascular endothelial growth factor receptor, Middle Aged, Immunohistochemistry, 3. Good health, Vascular endothelial growth factor A, Oncology, Vascular endothelial growth factor C, 030220 oncology & carcinogenesis, Female, Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Adolescent, Antineoplastic Agents, 03 medical and health sciences, Paracrine signalling, Young Adult, Humans, Autocrine signalling, 030304 developmental biology, Aged, Neoplasm Staging, Retrospective Studies, Settore MED/06 - ONCOLOGIA MEDICA, business.industry, Thymus Neoplasms, Receptors, Vascular Endothelial Growth Factor, chemistry, Cancer cell, Cancer research, biology.protein, business
Abstract

Objectives Tumor angiogenesis is an essential and complex process necessary for the growth of all tumors which represents a potential therapeutic target. Angiogenesis inhibitors targeting vascular endothelial growth factor (VEGF) or their receptor tyrosine kinases have been approved by the FDA. In thymic epithelial tumors (TET), targeted therapies have been sporadically applied due to their rarity. To ascertain the presence of potential therapeutic targets, we analyzed by immunohistochemistry the expression of angiogenesis-related biomarkers in a large series of TET arranged in Tissue Micro Arrays (TMA). Materials and methods We assessed by immunohistochemistry the expression of the possible molecular target of anti-angiogenic therapy, i.e. VEGFA, VEGFC, VEGFD, VEGFR1, VEGFR2, VEGFR3, and PDGFRβ, in a TMA series of 200 TET collected in the framework of a multi-institutional collaborative project for Rare Diseases. Results When compared to the low-risk tumors, high-risk TET (B2, B3, carcinomas) contained higher proportion of cancer cells expressing VEGFA, VEGFC and VEGFD ( P P P P =0.002), VEGFR2 ( P =0.013), and VEGFR3 ( P =0.041). No differences were observed in terms of PDGFRβ expression. Conclusions According to our data, it is possible to hypothesize the existence of multiple paracrine and/or autocrine loops in TET, particularly in the high-risk ones, involved in TET growth and progression. Anti-angiogenic agents, directed to inhibit these loops, are therefore to be considered as potential tools in advanced TET therapy.

Published
2014

27. JAK2V617F, CALR, and MPL Mutations and Bone Marrow Histology in Patients with Essential Thrombocythaemia.

Author

Pich, Achille, Riera, Ludovica, Francia di Celle, Paola, Beggiato, Eloise, Benevolo, Giulia, and Godio, Laura

Subjects
*MEGAKARYOCYTES, *GENETIC mutation, *THROMBOCYTOPENIA, *BONE marrow, *MUSCLE dysmorphia
Abstract

Introduction: Mutations in the JAK2, CALR, and MPL genes have been shown to have prognostic value in essential thrombocythaemia (ET), but no clear association with morphological changes has been reported so far. We investigated the possible correlation between gene mutations and histopathological features in bone marrow (BM) biopsies of patients with ET. Methods: Marrow cellularity, fibrosis, and the number of total and dysmorphic megakaryocytes and clusters of megakaryocytes were compared to gene mutations in 90 cases of ET at diagnosis. Results: The JAK2V617F mutation was found in 58.9%, CALR in 28.9%, and MPL in 4.4% of the cases, and 7.8% were triple-negative. JAK2V617F-mutated ET showed a high BM cellularity, the lowest number of clusters of megakaryocytes and the highest number of dysmorphic megakaryocytes; CALR-mutated ET showed a reduced BM cellularity, many clusters of large megakaryocytes, and very few dysmorphic megakaryocytes; MPL-mutated ET showed the lowest BM cellularity, the highest number of clustered and large megakaryocytes, and the lowest number of dysmorphic megakaryocytes. Triple-negative ET cases had the highest BM cellularity. Conclusions: Distinct morphological patterns were associated with gene mutations in ET, supporting the classification of ET into different subtypes. [ABSTRACT FROM AUTHOR]

Published
2018
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32. Expression of angiogenesis-related biomarkers in thymic epithelial tumors (TET)

Author

Marino, M, Lattanzio, R, Lauriola, L, Martucci, R, Sioletic, S, Gallo, E, Palmieri, G, Evoli, A, Granone, P, Palestro, Giorgio, Chiarle, Roberto, Barreca, A, Pich, Achille, Remotti, D, Pisa, R, Martelli, M, Truini, M, Ascani, S, Ruco, L, Rendina, Ea, Tunesi, G, Antimi, M, Lalle, M, Carlini, S, Facciolo, F, and Piantelli, M.

Subjects
angiogenesis, biomarkers, thymic epithelial tumors
Published
2010

45. Thymic epithelial tumors express vascular endothelial growth factors and their receptors as potential targets of antiangiogenic therapy: A tissue micro array-based multicenter study

Author

Lattanzio, Rossano, primary, La Sorda, Rossana, additional, Facciolo, Francesco, additional, Sioletic, Stefano, additional, Lauriola, Libero, additional, Martucci, Robert, additional, Gallo, Enzo, additional, Palmieri, Giovannella, additional, Evoli, Amelia, additional, Alessandrini, Gabriele, additional, Ruco, Luigi, additional, Rendina, Erino Angelo, additional, Truini, Mauro, additional, Chiarle, Roberto, additional, Barreca, Antonella, additional, Pich, Achille, additional, Ascani, Stefano, additional, Remotti, Daniele, additional, Tunesi, Gianni, additional, Granone, Pierluigi, additional, Ratto, Giovanni Battista, additional, Puma, Francesco, additional, Pescarmona, Edoardo, additional, Piantelli, Mauro, additional, Marino, Mirella, additional, Carlini, Sandro, additional, Cerasoli, Virna, additional, Corzani, Felicita, additional, Melis, Enrico, additional, Filippetti, Massimo, additional, Canalini, Paola, additional, Palestro, Giorgio, additional, Lalle, Maurizio, additional, Ruffini, Enrico, additional, Ceribelli, Anna, additional, and Rinaldi, Massimo, additional

Published
2014
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