Experimental oncology

B-Cell Neoplasia

Group leader

Paolo Ghia

Unit research activity is aimed at understanding the molecular mechanisms responsible for the onset and progression of B cell lymphoproliferative disorders (leukemia and lymphomas), which represent most of the neoplasms of the immune system, accounting for 10% of all types of cancer. To this aim, the Unit intends to identify molecules and signal transduction pathways relevant to leukemic progression and that can potentially be used as diagnostic markers, prognostic factors or new potential therapeutic targets. To this end, research methodology is based on the integration of experimental results obtained, in vitro and in vivo, from the study of normal and neoplastic B lymphocytes.

This approach originates on the evidence that a better understanding of the physiological mechanisms of the immune system is essential to achieve a deeper understanding of the process of neoplastic transformation of B lymphocytes.

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Research activity

In recent years, the unit has been particularly interested in the pathogenesis of Chronic Lymphocytic Leukemia (CLL), the most frequent adult leukemia in the Western world. Group research activity is focused on the fundamental role played by the microenvironment in the pathogenesis of the disease by studying the surrounding non-neoplastic cells and the molecular interactions occurring with the leukemic clone that are responsible for the survival and expansion of the leukemia. Particular attention is given by our laboratory to the definition of the role played by the antigen receptor (B Cell Receptor) and its interaction with foreign or self antigens.

Furthermore, the unit has described the existence of a pre- leukemic condition named Monoclonal B lymphocytosis (MBL) which is being studied by this group, from a genetic and molecular point of view, as a model of tumor progression.

Selected publications

Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, Kaplan P, Kraychok I, Illes A, de la Serna J, Dolan S, Campbell P, Musuraca G, Jacob A, Avery E, Lee JH, Liang W, Patel P, Quah C, Jurczak W. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 May 27:JCO1903355. doi: 10.1200/JCO.19.03355.

Agathangelidis A, Galigalidou C, Scarfò L, Moysiadis T, Rovida A, Vlachonikola E, Sofou E, Psomopoulos F, Vardi A, Ranghetti P, Siorenta A, Galanis A, Stamatopoulos K, Chatzidimitriou A, Ghia P. High-throughput analysis of the T cell receptor gene repertoire in low-count monoclonal B cell lymphocytosis reveals a distinct profile from chronic lymphocytic leukemia. Haematologica. 2020 Jan 16:haematol.2019.221275

Gounari M, Ntoufa S, Gerousi M, Vilia MG, Moysiadis T, Kotta K, Papakonstantinou N, Scarfò L, Agathangelidis A, Fonte E, Ranghetti P, Nenou A, Xochelli A, Coscia M, Tedeschi A, Stavroyianni N, Muzio M, Stamatopoulos K, Ghia P. Dichotomous Toll-like receptor responses in chronic lymphocytic leukemia patients under ibrutinib treatment. Leukemia. 2019 Apr;33(4):1030-1051

Minici C, Gounari M, Übelhart R, Scarfò L, Dühren-von Minden M, Schneider D, Tasdogan A, Alkhatib A, Agathangelidis A, Ntoufa S, Chiorazzi N, Jumaa H, Stamatopoulos K, Ghia P*, Degano M* (*Co-senior authors). Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia. Nat Commun. 2017 Jun 9;8:15746

Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR, Hillmen P, Stephens DM, Ghia P, Barrientos JC, Pagel JM, Woyach J, Johnson D, Huang J, Wang X, Kaptein A, Lannutti BJ, Covey T, Fardis M, McGreivy J, Hamdy A, Rothbaum W, Izumi R, Diacovo TG, Johnson AJ, Furman RR. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32.

Minici C, Gounari M, Übelhart R, Scarfò L, Dühren-von Minden M, Schneider D, Tasdogan A, Alkhatib A, Agathangelidis A, Ntoufa S, Chiorazzi N, Jumaa H, Stamatopoulos K, Ghia P*, Degano M. Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia. Nat Commun. 2017 Jun 9;8:15746.

McMahon KM, Scielzo C, Angeloni NL, Deiss-Yehiely E, Scarfo L, Ranghetti P, Ma S, Kaplan J, Barbaglio F, Gordon LI, Giles FJ, Shad Thaxton C, Ghia P. Synthetic high-density lipoproteins as targeted monotherapy for chronic lymphocytic leukemia. Oncotarget. 2017 Feb 14;8(7):11219-11227.

Stamatopoulos K, Agathangelidis A, Rosenquist R, Ghia P. Antigen receptor stereotypy in chronic lymphocytic leukemia. Leukemia. 2017 Feb;31(2):282-291.

Rawstron AC, Fazi C, Agathangelidis A, Villamor N, Letestu R, Nomdedeu J, Palacio C, Stehlikova O, Kreuzer KA, Liptrot S, O'Brien D, de Tute RM, Marinov I, Hauwel M, Spacek M, Dobber J, Kater AP, Gambell P, Soosapilla A, Lozanski G, Brachtl G, Lin K, Boysen J, Hanson C, Jorgensen JL, Stetler-Stevenson M, Yuan C, Broome HE, Rassenti L, Craig F, Delgado J, Moreno C, Bosch F, Egle A, Doubek M, Pospisilova S, Mulligan S, Westerman D, Sanders CM, Emerson R, Robins HS, Kirsch I, Shanafelt T, Pettitt A, Kipps TJ, Wierda WG, Cymbalista F, Hallek M, Hillmen P, Montserrat E, Ghia P. A complementary role of multiparameter flow-cytometry and high-throughput sequencing for minimal residual disease (MRD) detection in chronic lymphocytic leukemia (CLL): An european research initiative on CLL (ERIC) study. Leukemia. 2016 Apr;30(4):929-36.

Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O'Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ. RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with Chronic lymphocytic leukemia. N Engl J Med. 2015 Dec 17;373(25):2425-37.

Gounari M, Ntoufa S, Apollonio B, Papakonstantinou N, Ponzoni M, Chu CC, Rossi D, Gaidano G, Chiorazzi N, Stamatopoulos K, Ghia P. Excessive antigen reactivity may underlie the clinical aggressiveness of chronic lymphocytic leukemia stereotyped subset 8. Blood. 2015 Jun 4;125(23):3580-7.

Simonetti G, Bertilaccio MT, Veliz Rodriguez T, Apollonio B, Dagklis A, Rocchi M, Innocenzi A, Casola S, Winkler TH, Nitschke L, Ponzoni M, Caligaris-Cappio F, Ghia P. SIGLEC-G deficiency increases susceptibility to develop B-cell lymphoproliferative disorders. Haematologica. 2014 Aug;99(8):1356-64.

Vardi A, Dagklis A, Scarfò L, Jelinek D, Newton D, Bennett F, Almeida J, Rodriguez-Caballero A, Allgood S, Lanasa M, Cortelezzi A, Orlandi E, Veronese S, Montillo M, Rawstron A, Shanafelt T, Orfao A, Stamatopoulos K, Ghia P. Immunogenetics shows that not all MBL are equal: the larger the clone the more similar to CLL. Blood. 2013;121:4521-4528.

Dagklis A, Ponzoni M, Govi S, Cangi MG, Pasini E, Charlotte F, Vino A, Doglioni C, Davì F, Lossos IS, Ntountas I, Papadaki T, Dolcetti R, Ferreri AJ, Stamatopoulos K, Ghia P. Immunoglobulin gene repertoire in ocular adnexal lymphomas: hints on the nature of the antigenic stimulation. Leukemia. 2012;26:814-821.

Fazi C, Scarfò L, Pecciarini L, Cottini F, Dagklis A, Janus A, Talarico A, Scielzo C, Sala C, Toniolo D, Caligaris-Cappio F, Ghia P. General population low-count CLL-like MBL persist over time without clinical progression, though carrying the same cytogenetic abnormalities of CLL. Blood. 2011;118:6618-6625.