Paolo Ghia
Paolo Ghia
affiliation: Università Vita-Salute San Raffaele
research area(s): Cancer Biology, Immunity And Infection
Course: Basic and Applied Immunology
University/Istitution: Università Vita-Salute San Raffaele
1984-1990 MD Degree, University of Torino, Torino, Italy
1991-1994 PhD Degree, Human Oncology, University of Torino, Torino, Italy
1998-2003 Residency, Internal Medicine - University of Torino, Torino, Italy.

Professional experiences
1993 - 1996 Postdoctoral Fellow, Basel Institute for Immunology, Basel, Switzerland
1996 - 1998 Research Associate, Harvard Medical School, DFCI, Boston, MA, USA
1998 - 2005 Assistant Professor of Internal Medicine, University of Torino, Torino, Italy
2003 - 2004 Chief, Cancer Immunology Lab, Institute for Cancer Research and Treatment, Candiolo, Italy
2005 - 2010 Assistant Professor of Internal Medicine, Università Vita-Salute San Raffaele, Milano, Italy
2005 - today Scientific coordinator, Lymphoma Unit, San Raffaele Scientific Institute, Milano, Italy
2009 - today Head of Unit, B Cell Neoplasia, San Raffaele Scientific Institute, Milano, Italy
2010 - today: Associate Professor of Internal Medicina, Università Vita-Salute San Raffaele, Milano
The main focus of our scientific activity is on tumors of mature B lymhocytes and in particular on tumours of the chronic type that are virtually incurable, aiming at identifying relevant molecules and pathways that can be selectively targeted for therapeutic purposes in a patient-tailored fashion.
Our present research activity originates from the evidence that the raison d"etre of mature B cells is the expression of a B cell antigen receptor (BCR). Growing experimental evidence indicates that antigen stimulation may favour the onset and expansion of a number of chronic B-cell malignancies. Our research activity aims at understanding the relationship between Ag stimulation and malignant transformation in B-cell tumours.
An important model to understand these relationships is Chronic Lymphocytic Leukaemia (CLL), the most common adult B-cell leukemia in the western world. All experimental data indicate that CLL B cells experience some degree of antigenic exposure. The nature of the stimulation is currently studied in our Unit.
In addition, the normal cellular counterpart of CLL cells is not yet known and the actual stage of differentiation at which the antigenic exposure occurs is poorly defined. We and others have previously described the existence of monoclonal B cells circulating in the peripheral blood of 6.7% of otherwise healthy adult individuals. These lymphocytes phenotypically resemble CLL cells and this entity is now defined as Monoclonal B-cell Lymphocytosis (MBL). Its frequency increases with age, becoming 45% in individuals older than 90. We are currently studying the biological relationship between MBL and CLL, with the aim of identifying the molecular and functional features that can distinguish the two entities and may help to discriminate the individuals at risk of leukemic evolution. This is currently studied also through the use of specific mouse models.
Scarfò L, Dagklis A, Scielzo C, Fazi C, Ghia P. (2010) CLL-like monoclonal B-cell lymphocytosis: are we all bound to have it? Semin Cancer Biol;20:384-390

Bertilaccio MT, Scielzo C, Simonetti G, Ponzoni M, Apollonio B, Fazi C, Scarfò L, Rocchi M, Muzio M, Caligaris-Cappio F, Ghia P. (2010) A novel Rag2-/-gammac-/--xenograft model of human CLL. Blood;115:1605-9.

Darzentas N, Hadzidimitriou A, Murray F, Hatzi K, Josefsson P, Laoutaris N, Moreno C, Anagnostopoulos A, Jurlander J, Tsaftaris A, Chiorazzi N, Belessi C, Ghia P*, Rosenquist R, Davi F, Stamatopoulos K. (2010) A different ontogenesis for chronic lymphocytic leukemia cases carrying stereotyped antigen receptors: molecular and computational evidence. *corresponding author. Leukemia;24:125-32 3.

Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. (2009) The microenvironment in mature B-cell malignancies: a target for new treatment strategies.Blood;114:3367-75

Landgren O, Albitar M, Ma W, Abbasi F, Hayes RB, Ghia P, Marti GE, Caporaso NE. (2009) B-cell clones as early markers for chronic lymphocytic leucemia. N Engl J Med;360:659-667.

Dagklis A, Fazi C, Sala C, Cantarelli V, Scielzo C, Massacane R, Toniolo D, Caligaris-Cappio F, Stamatopoulos K, Ghia P. (2009) The immunoglobulin gene repertoire of low-count CLL-like MBL is different from CLL: diagnostic implications for clinical monitoring. Blood;114:26-32

Ghia P, Chiorazzi N, Stamatopoulos K. (2008) Microenvironmental influences in chronic lymphocytic leukaemia: the role of antigen stimulation. J Intern Med;264:549-562.

Caligaris-Cappio F, Ghia P. (2008) Novel insights in chronic lymphocytic leukemia: are we getting closer to understanding the pathogenesis of the disease? J Clin Oncol;26:4497-4503.

Muzio M, Apollonio B, Scielzo C, Frenquelli M, Vandoni I, Boussiotis V, Caligaris-Cappio F, Ghia P. (2008) Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy. Blood;112:188-195.

Murray F, Darzentas N, Hadzidimitriou A, Tobin G, Boudjogra M, Scielzo C, Laoutaris N, Karlsson K, Baran-Marzsak F, Tsaftaris A, Moreno C, Anagnostopoulos A, Caligaris-Cappio F, Vaur D, Ouzounis C, Belessi C, Ghia P*, Davi F, Rosenquist R, Stamatopoulos K. (2008) Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis. *corresponding author. Blood;111:1524-1533.

Ghia P, Stamatopoulos K, Belessi C, Moreno C, Stilgenbauer S, Stevenson F, Davi F, Rosenquist R. (2007) ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leucemia. Leukemia;21:1-3.

Stamatopoulos K, Belessi C, Moreno C, Boudjograh M, Guida G, Smilevska T, Belhoul L, Stella S, Stavroyianni N, Crespo M, Hadzidimitriou A, Sutton L, Bosch F, Laoutaris N, Anagnostopoulos A, Montserrat E, Fassas A, Dighiero G, Caligaris-Cappio F, Merle-Béral H, Ghia P*, Davi F. (2007) Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: pathogenetic implications and clinical correlations. *corresponding author and shared last authorship Blood;109:259-270.

Belessi CJ, Davi FB, Stamatopoulos KE, Degano M, Andreou TM, Moreno C, Merle-Beral H, Crespo M, Laoutaris NP, Montserrat E, Caligaris-Cappio F, Anagnostopoulos AZ, Ghia P. (2006) IGHV gene insertions and deletions in chronic lymphocytic leukemia: "CLL-biased" deletions in a subset of cases with stereotyped receptors. Eur J Immunol;36:1963-1974.

Scielzo C, Camporeale A, Geuna M, Alessio M, Poggi A, Zocchi MR, Chilosi M, Caligaris-Cappio F, Ghia P. (2006) ZAP-70 is expressed by normal and malignant human B-cell subsets of different maturational stage. Leukemia;20:689-695.
Project Title:
Inhibition of signalling pathways crucial foe the pathogenesis of Lymphoproliferative disorders: in vitro dissection of mechanisms of action and in vi
Background and rationale
The molecular dissection of signalling pathways in B Cell Neoplasias have led to a substantial understanding of the mechanisms acting in the pathogenesis of these diseases. We have previously studied Chronic Lymphocytic Leukemias (CLL), a disorder characterized by the accumulation of mature B lymphocytes and we have shown the existence of constitutive activation of several signalling molecules downstream the Immunoglobulin receptor (BCR) and other co-stimulatory molecules as CD40. These evidences suggest that stimuli originating from the microenvironment are involved in the onset and maintenance of the neoplastic cell clone.

Specific aims and methodology
The aim of this project is to further dissect the signalling pathways active in CLL as well as other B lymphoid disorders and to exploit this knowledge for testing novel therapeutic strategies based on the specific inhibition of crucial pathways using inhibitory compounds both in vitro and in vivo, taking advantage of dedicated animal models. In particular we are planning to perform:
- A biochemical characterization of signalling pathways active in CLL and other lymphoproliferative disorders.
- An analysis of the efficacy of specifically-designed inhibitory compounds on the modulation of microenvironmental stimuli in primary leukemic B cells (in vitro models)
- An analysis of the efficacy of specifically-designed inhibitory compounds on the modulation of microenvironmental stimuli in dedicated mouse models (in vivo models)

Expected results
Definition of novel therapeutic approaches in B cell Neoplasias following tailored targeting of active signalling pathways crucial for the maintenance of the disease.

Project Title:
From activation to transformation: the (in)evitable fate of a B lymphocyte
Background and rationale
We recently identified a novel B cell subpopulation circulating in the peripheral blood of otherwise healthy individuals. These cells have a distinct phenotype (CD19+, CD20low, CD5+) resembling Chronic Lymphocytic Leukemia (CLL), the most common adult leukemia. In most cases they are monoclonal though being a tiny minority of all circulating B lymphocytes. This entity is defined Monoclonal B-cell lymphocytosis (MBL) and its frequency increases with age, becoming >10% in individuals older than 75 years and almost 50% above 90 years of age.
Several evidences helped to propose the hypothesis that these cells may be due to the senescence of the immune system, likely following the chronic exposition to persistent infectious agents (e.g. viruses) and/or self-antigens. Only a minority of cases will eventually evolve into a frank leukemia, thereby providing a unique model to study how B cell activation in a specific context may lead to a neoplastic transformation.

Specific aims and methodology
The aim of this project is to characterize at genetic, biochemical and functional level this novel B cell population and to understand the potential relationship with immunosenescence and neoplastic transformation. In particular we are planning to:
���� characterize the MBL cells through genome-wide analysis and next-generation sequencing technology
- analyze in vivo the origin of MBL utilizing specific mouse models, already available in the lab.
���� characterize the genetic and functional features of human MBL that can distinguish it from CLL and may help to discriminate the individuals at risk of leukemic evolution.

Expected results
A thorough molecular characterization of the MBL cells, as an example of early steps of leukemogenesis; the definition of their physiological role in vivo; the identification of molecular markers that can be exploited for diagnostic and prognostic purposes to predict the cases with a higher risk of transformation.