IOR Institute of Oncology Research

Bellinzona, Switzerland

IOR Institute of Oncology Research

Bellinzona, Switzerland
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Boi M.,New York Medical College | Boi M.,New York University | Zucca E.,IOSI Oncology Institute of Southern Switzerland | Inghirami G.,New York Medical College | And 4 more authors.
British Journal of Haematology | Year: 2015

Summary: The currently used 2008 World Health Organization classification recognizes two types of systemic anaplastic large T cell lymphoma according to ALK protein expression in tumour cells. First, the 'anaplastic large cell lymphoma, ALK positive' (ALK+ ALCL) that is characterized by the presence of ALK gene rearrangements and consequent ALK protein expression, and, second, the 'anaplastic large cell lymphoma, ALK negative' (ALK- ALCL) that is a provisional entity lacking ALK protein expression but cannot be distinguished morphologically from ALK+ ALCL. In this review we summarize the current knowledge on the genetic lesions and biological features that underlie the pathogenesis of ALK+ and the ALK- ALCL and that can lead to the use of targeted anti-cancer agents. © 2015 John Wiley & Sons Ltd.

Tabbo F.,University of Turin | Ponzoni M.,San Raffaele Scientific Institute | Rabadan R.,Columbia University | Bertoni F.,IOR Institute of Oncology Research | And 2 more authors.
Current Opinion in Hematology | Year: 2013

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. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Zucca E.,Southern Research Institute | Bertoni F.,Southern Research Institute | Bertoni F.,IOR Institute of Oncology Research | Vannata B.,Southern Research Institute | Cavalli F.,Southern Research Institute
Clinical Cancer Research | Year: 2014

Extranodal marginal zone B-cell lymphomas of the mucosa-associated lymphoid tissue (MALT) arise from lymphoid populations that are induced by chronic inflammation in extranodal sites. The most frequently affected organ is the stomach, where MALT lymphoma is incontrovertibly associated with a chronic gastritis induced by a microbial pathogen, Helicobacter pylori. Gastric MALT lymphoma therefore represents a paradigm for evaluating inflammation-associated lymphomagenesis, which may lead to a deeper understanding of a possible etiologic association between other microorganisms and nongastric marginal zone lymphomas. Besides infectious etiology, chronic inflammation caused by autoimmune diseases, such as Sjögren syndrome or Hashimoto thyroiditis, can also carry a significant risk factor for the development of marginal zone lymphoma. In addition to the continuous antigenic drive, additional oncogenic events play a relevant role in lymphoma growth and progression to the point at which the lymphoproliferative process may eventually become independent of antigenic stimulation. Recent studies on MALT lymphomas have in fact demonstrated genetic alterations affecting the NF-κB) pathway, a major signaling pathway involved in many cancers. This review aims to present marginal zone lymphoma as an example of the close pathogenetic link between chronic inflammation and tumor development, with particular attention to the role of infectious agents and the integration of these observations into everyday clinical practice. ©2014 AACR.

Chila R.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Basana A.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Lupi M.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Guffanti F.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | And 10 more authors.
Oncotarget | Year: 2015

Mantle cell lymphoma (MCL) is an aggressive, incurable disease, characterized by a deregulated cell cycle. Chk1 and Wee1 are main regulators of cell cycle progression and recent data on solid tumors suggest that simultaneous inhibition of these proteins has a strong synergistic cytotoxic effect. The effects of a Chk1 inhibitor (PF-00477736) and a Wee1 inhibitor (MK-1775) have been herein investigated in a large panel of mature B-cell lymphoma cell lines. We found that MCL cells were the most sensitive to the Chk1 inhibitor PF-00477736 and Wee1 inhibitor MK-1775 as single agents. Possible involvement of the translocation t(11;14) in Chk1 inhibitor sensitivity was hypothesized. The combined inhibition of Chk1 and Wee1 was strongly synergistic in MCL cells, leading to deregulation of the cell cycle, with increased activity of CDK2 and CDK1, and activation of apoptosis. In vivo treatment with the drug combination of mice bearing JeKo-1 xenografts (MCL) had a marked antitumor effect with tumor regressions observed at non-toxic doses (best T/C%=0.54%). Gene expression profiling suggested effect on genes involved in apoptosis. The strong synergism observed by combining Chk1 and Wee1 inhibitors in preclinical models of MCL provides the rationale for testing this combination in the clinical setting.

Aprile von Hohenstaufen K.,IOSI Oncology Institute of Southern Switzerland | Conconi A.,University of Piemonte Orientale | de Campos C.P.,Dalle Molle Institute for Artificial Intelligence | de Campos C.P.,IOR Institute of Oncology Research | And 10 more authors.
British Journal of Haematology | Year: 2013

An increased number of circulating monocytes at presentation has recently been associated with shorter survival in Hodgkin lymphoma, follicular lymphoma and diffuse large B cell lymphoma. This study aimed to assess the prognostic impact of the absolute monocyte count (AMC) at diagnosis in mantle cell lymphoma (MCL). AMC at diagnosis was available in 97 MCL cases recorded in the databases of the Oncology Institute of Southern Switzerland in Bellinzona (Switzerland) and the Division of Haematology of the Amedeo Avogadro University of Eastern Piedmont in Novara (Italy). With a median follow up of 7 years, the 5-year overall survival was 29% for patients with AMC >0·50 × 109/l and 62% for patients with AMC ≤0·50 × 109/l (P = 0·008). Elevated AMC and beta-2 microglobulin at diagnosis remained independent outcome predictors at multivariate analysis, controlling for the MCL International Prognostic Index (MIPI), and have been used to build a simple prognostic scoring system. In this relatively small and heterogeneous series an increased AMC identified poor-risk patients. Our results suggest that AMC together with the beta-2 microglobulin level might provide an inexpensive way to stratify MCL patient risk as a complement to the MIPI, which was confirmed to be a very powerful prognostic tool. © 2013 John Wiley & Sons Ltd.

Lagana A.,Ohio State University | Acunzo M.,Ohio State University | Romano G.,Ohio State University | Pulvirenti A.,University of Catania | And 8 more authors.
Nucleic Acids Research | Year: 2014

RNAi is a powerful tool for the regulation of gene expression. It is widely and successfully employed in functional studies and is now emerging as a promising therapeutic approach. Several RNAi-based clinical trials suggest encouraging results in the treatment of a variety of diseases, including cancer. Here we present miR-Synth, a computational resource for the design of synthetic microRNAs able to target multiple genes in multiple sites. The proposed strategy constitutes a valid alternative to the use of siRNA, allowing the employment of a fewer number of molecules for the inhibition of multiple targets. This may represent a great advantage in designing therapies for diseases caused by crucial cellular pathways altered by multiple dysregulated genes. The system has been successfully validated on two of the most prominent genes associated to lung cancer, c-MET and Epidermal Growth Factor Receptor (EGFR). (See © 2014 The Author(s) 2014.

Testoni M.,IOR Institute of Oncology Research | Zucca E.,IOSI Oncology Institute of Southern Switzerland | Young K.H.,University of Houston | Bertoni F.,IOR Institute of Oncology Research | Bertoni F.,IOSI Oncology Institute of Southern Switzerland
Annals of Oncology | Year: 2015

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults, accounting for 35%-40% of all cases. The combination of the anti-CD20 monoclonal antibody rituximab with anthracycline-based combination chemotherapy (R-CHOP, rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone) lead to complete remission in most and can cure more than half of patients with DLBCL. The diversity in clinical presentation, as well as the pathologic and biologic heterogeneity, suggests that DLBCL comprises several disease entities that might ultimately benefit from different therapeutic approaches. In this review, we summarize the current literature focusing on the genetic lesions identified in DLBCL. © 2014 The Author.

Testoni M.,IOR Institute of Oncology Research | Chung E.Y.L.,IOR Institute of Oncology Research | Priebe V.,IOR Institute of Oncology Research | Bertoni F.,IOR Institute of Oncology Research | Bertoni F.,IOSI Oncology Institute of Southern Switzerland
Leukemia and Lymphoma | Year: 2015

ETS1 is a member of the ETS family of transcription factors, which contains many cancer genes. ETS1 gene is mapped at 11q24.3, a chromosomal region that is often the site of genomic rearrangements in hematological cancers. ETS1 is expressed in a variety of cells, including B and T lymphocytes. ETS1 is important in various biological processes such as development, differentiation, proliferation, apoptosis, migration and tissue remodeling. It acts as an oncogene controlling invasive and angiogenic behavior of malignant cells in multiple human cancers. In particular, ETS1 deregulation has been reported in diffuse large B-cell lymphoma, in Burkitt lymphoma and in Hodgkin lymphoma. Here, we summarize the function of ETS1 in normal cells, with a particular emphasis on lymphocytes, and its possible role as an oncogene or tumor suppressor gene in the different mature B cell lymphomas. © 2015 Informa UK, Ltd.

Chigrinova E.,IOR Institute of Oncology Research
Blood | Year: 2013

Richter syndrome (RS) occurs in up to 15% of patients with chronic lymphocytic leukemia (CLL). Although RS, usually represented by the histologic transformation to a diffuse large B-cell lymphoma (DLBCL), is associated with a very poor outcome, especially when clonally related to the preexisting CLL, the mechanisms leading to RS have not been clarified. To better understand the pathogenesis of RS, we analyzed a series of cases including 59 RS, 28 CLL phase of RS, 315 CLL, and 127 de novo DLBCL. RS demonstrated a genomic complexity intermediate between CLL and DLBCL. Cell-cycle deregulation via inactivation of TP53 and of CDKN2A was a main mechanism in the histologic transformation from CLL phase, being present in approximately one half of the cases, and affected the outcome of the RS patients. A second major subgroup was characterized by the presence of trisomy 12 and comprised one third of the cases. Although RS shared some of the lesions seen in de novo DLBCL, its genomic profile was clearly separate. The CLL phase preceding RS had not a generalized increase in genomic complexity compared with untransformed CLL, but it presented clear differences in the frequency of specific genetic lesions.

Boi M.,IOR Institute of Oncology Research
Blood | Year: 2013

Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that can present as a systemic or primary cutaneous disease. Systemic ALCL represents 2% to 5% of adult lymphoma but up to 30% of all pediatric cases. Two subtypes of systemic ALCL are currently recognized on the basis of the presence of a translocation involving the anaplastic lymphoma kinase ALK gene. Despite considerable progress, several questions remain open regarding the pathogenesis of both ALCL subtypes. To investigate the molecular pathogenesis and to assess the relationship between the ALK(+) and ALK(-) ALCL subtypes, we performed a genome-wide DNA profiling using high-density, single nucleotide polymorphism arrays on a series of 64 cases and 7 cell lines. The commonest lesions were losses at 17p13 and at 6q21, encompassing the TP53 and PRDM1 genes, respectively. The latter gene, coding for BLIMP1, was inactivated by multiple mechanisms, more frequently, but not exclusively, in ALK(-)ALCL. In vitro and in vivo experiments showed that that PRDM1 is a tumor suppressor gene in ALCL models, likely acting as an antiapoptotic agent. Losses of TP53 and/or PRDM1 were present in 52% of ALK(-)ALCL, and in 29% of all ALCL cases with a clinical implication.

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