Non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoid malignancies and it is the fourth most common malignancy across the pediatric age spectrum. Our research area of interest is dedicated mainly to the study and characterization of NHL of childhood. The general approach includes the analysis of molecular mechanisms of tumorigenesis with a translational approach aimed at transferring biological results from the bench to clinical trials. This includes also the study of new tumor specific markers for the diagnosis and the prognosis of various malignancies and the study of liquid biopsies.
On-going projects include:
i) identification of new biomarkers in liquid biopsy of pediatric patients with Burkitt lymphoma (BL):BL is the most frequent subtype of NHL occurring in children and adolescents, representing more than half of childhood lymphomas. Probability of survival for refractory and relapse is very poor. Novel biomarkers are required to better understand the disease heterogeneity and the mechanism of relapse/progression. The aim of this study is to elucidate the prognostic role of liquid biopsy in particular to evaluate cell free DNA as marker of disease progression, and to characterize cells that constitute Minimal Residual Disease, in terms of side population, with gene expression analysis and single cell sequencing.
ii) OMICS-driven characterization of pediatric CD30 positive lymphomas: from tumor biopsy to tumor microenvironment: Hodgkin lymphoma (HL) and Anaplastic Large Cell Lymphoma (ALCL) are both CD30 positive lymphomas accounting for ~10% and 3% of all cases of lymphoid neoplasms, respectively. A field of interest that has grown exponentially in the last few years, impacting various areas of research, is the extracellular vesicle (EV) study, in particular of small EVs formed inside endosomal compartments (i.e., exosomes). Exosomes are actively released vesicles (carrying RNA, DNA and protein) that can function as inter-cellular messengers. The principal aims of this project are 1) to characterize the exosomes at the transcriptional level, comparing them with transcriptional data obtained from primitive tumor cells; 2) to provide insights on communication mechanisms between cancer cells and the microenvironment and 3) to perform an extensive research on the proteomic composition of cancer cell-derived exosomes, to define their role in disease progression and/or resistance.
iii) metabolic profiling of diffuse large B-cell lymphomas: bench-to-bedside characterization of TRAP1 oncogenic role: diffuse large B-cell lymphomas (DLBCLs) are a heterogeneous group of aggressive lymphoid neoplasms. The present study will address the many open issues concerning the metabolic reprogramming of DLBCL and its clinical, prognostic and therapeutic implications. Pre-clinical and pathological studies will specifically consider the oncogenic role of TRAP1, an emerging master regulator of tumor cell metabolism.
Recent achievements from the group include: i)the genomics-driven identification of molecular mechanisms and biomarkers in pediatric follicular lymphoma: Follicular lymphoma (FL) is the second most common histological subtype of non-Hodgkin lymphoma (NHL) of adulthood; pediatric FL (pFL) has recently been recognized as a novel variant of FL in the World Health Organization classification of lymphoma, accounting for not more than 2-3% of NHLs in this age group. We analyzed the mutational landscape of pFL by exome sequencing of a series of tumour biopsies and our network analysis considerably extended previous data on the mutational landscape of FL of pediatric age, further indicating the signaling pathways of possible pathogenic relevance in these malignancies, (Lovisa F, Haematol 2019); ii) the characterization of miRNA profiles associated with ALCL primary tumors: we demonstrated that miR-939 expression could contribute to PDGFRB inhibition, a crucial driver for ALCL lymphomagenesis, via JUNB downregulation (Garbin A, Haematol 2020).
Federica Lovisa, senior Post-doctoral fellows
Lavinia Ferrone, junior Post-doctoral fellows
Carlotta Damani, PhD students
Piero Di Battista, PhD students
Ilaria Gallingani, PhD students
Anna Garbin, PhD students
Elisa Tosato, Technician
Anna Tosato, Pre-graduate fellows
Anna Giada Toniolo, Pre-graduate fellows
Lisa Quartesan, Pre-graduate fellows
Mussolin L, Le Deley MC, Carraro E, Damm-Welk C, Attarbaschi A, Williams D, Burke A, Horibe K, Nakazawa A, Wrobel G, Mann G, Csóka M, Uyttebroeck A, Fernández-Delgado Cerdá RF, Beishuizen A, Mellgren K, Burkhardt B, Klapper W, Turner SD, D’Amore ESG, Lamant L, Reiter A, Woessmann W, Brugières L, Pillon Prognostic Factors in Childhood Anaplastic Large Cell Lymphoma: Long Term Results of the International ALCL99 Trial. Cancers. 2020 Sep 24;12(10);
Garbin A, Lovisa F, Holmes AB, Damanti CC, Gallingani I, Carraro E, Accordi B, Veltri G, Pizzi M, d’Amore ESG, Pillon M, Biffi A, Basso K, Mussolin L. miR-939 acts as tumor suppressor by modulating JUNB transcriptional activity in pediatric anaplastic large cell lymphoma. Haematologica, 2020;
Mussolin L, Lovisa F, Gallingani I, Cavallaro E, Carraro E, Damanti CC, Vinti L, Sala A, Micalizzi C, Santoro N, Piglione M, Cellini M, Buffardi S, Buldini B, D’Amore ESG, Biffi A, Pillon M. Minimal residual disease analysis in childhood mature B-cell leukaemia/lymphoma treated with AIEOP LNH-97 protocol with/without anti-CD20 administration. Br J Haematol, 2020;
Lovisa F, Binatti A, Coppe A, Primerano S, Carraro E, Pillon M, Pizzi M, Guzzardo V, Buffardi S, Porta F, Farruggia P, De Santis R, Bulian P, Basso G, Lazzari E, d’Amore ESG, Bortoluzzi S, Mussolin L. A high definition picture of key genes and pathways mutated in pediatric follicular lymphoma. Haematologica, 2019;
Mussolin L, Pillon M, Zimmermann M, Carraro E, Basso G, Knoerr F, WoessmannW, Damm-Welk C. Course of anti-ALK antibody titres during chemotherapy in children with anaplastic large cell lymphoma. Br J Haematol. 2018 Sep;182(5);
Pomari E, Basso G, Bresolin S, Pillon M, Carraro E, d’Amore ES, Viola G, Frasson C, Basso K, Bonvini P, Mussolin L. NPM-ALK expression levels identify two distinct subtypes of paediatric anaplastic large cell lymphoma. Leukemia, 2017;
Gambacorti-Passerini C, Mussolin L, Brugieres L. Abrupt Relapse of ALK-Positive Lymphoma after Discontinuation of Crizotinib. N Engl J Med. 2016;
Mussolin L, Holmes AB, Romualdi C, Sales G, D’Amore ES, Ghisi M, Pillon M, Rosolen A, Basso K. An aberrant microRNA signature in childhood T-celllymphoblastic lymphoma affecting CDKN1B expression, NOTCH1 and growth factor signaling pathways. Leukemia. 2014;
Mussolin L, Damm-Welk C, Pillon M, Zimmermann M, Franceschetto G, Pulford K, Reiter A, Rosolen A, Woessmann W. Use of minimal disseminated disease and immunity to NPM-ALK antigen to stratify ALK-positive ALCL patients with different prognosis. Leukemia. 2013;
Mussolin L, Pillon M, d’Amore ES, Conter V, Piglione M, Lo Nigro L, Garaventa A, Buffardi S, Aricò M, Rosolen A. Minimal disseminated disease in high-risk Burkitt’s lymphoma identifies patients with different prognosis. J Clin Oncol. 2011.
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