A multidisciplinary investigation into the pathogenesis of chronic lymphocytic leukemia (CLL) for the identification of novel molecular therapeutic targets
Funding Body: FONAZIONE CARIPLO
Foundation Funding, June 2010 –November 2012
The aim of this project is to investigate relevant pathogenetic mechanisms of Chronic lymphocytic leukemia (CLL) by dissecting the interactions occurring between the B Cell Receptor and yet unknown antigens. This will provide the basis for designing innovative and selective therapeutic strategies.
CLL is the most frequent leukemia among adults in the western world, due to the accumulation of mature neoplastic B lymphocytes. CLL is an incurable disease, despite the use of intensive and costly immuno-chemotherapeutic treatments, leading to great distress for patients and their families as well as huge social costs for both public and private health care systems. A way to overcome resistance to therapy will derive from a better understanding of the molecular mechanisms of the disease that may lead to the identification of novel molecular targets for therapy. CLL is considered as a typical multifactorial disease where genetic and (micro)environmental elements concur to its pathogenesis: genetic events play a relevant role in initiating CLL but it is evident that stimuli originating from the microenvironment are responsible for maintaining and propagating the disease. Therefore, CLL may be seen as a model to elucidate the pathogenesis of cancer in general as it may reveal common oncogenic pathways acting in other neoplastic diseases.
The key molecule for a B cell is the immunoglobulin (IG) that serves as a B cell–specific receptor (BCR) able to recognize distinct antigens (Ag). Gene expression profiling and functional experiments indicate that stimulation through the BCR is involved in the selection and expansion of the leukemic clone in CLL. More recently, several groups including ours have reported that CLL patients may express closely homologous if not identical (“stereotyped”) BCR, characterized by highly restricted complementarity-determining region 3 (CDR3) sequences. The CDR3 is the most relevant portion of the IG molecule, concurring to the definition and shaping of the antigen-binding site. As a consequence, the remarkable similarity of the BCR in unrelated and geographically distinct cases implies the recognition of individual, discrete antigens or classes of structurally similar epitopes, likely selecting the leukemic clones. This unexpected feature is a quite widespread molecular event in CLL as we have shown that over 100 different “stereotyped” motifs exist in CLL cases, accounting for almost 30% of the patients. Significantly, we and others have shown that the presence of particular “stereotyped” BCRs correlate with a distinct clinical outcome, regardless other prognostic markers, suggesting that a particular antigenic element binding to a distinctive receptor may be critical in modulating the natural history of the disease and determining clinical presentation. That notwithstanding, the precise nature of the Ag(s) recognized by CLL cells and their interactions with CLL progenitors or the malignant cells themselves remain shadowy and both foreign and auto-antigens have been suggested to be implicated. Based on these evidences, the definition of the actual nature of the antigen(s) recognized by the “stereotyped” BCRs has to be considered crucial for the elucidation of the in vivo stimulation sustaining the leukemic clones and for the design of innovative therapeutic strategies aiming at interfering with such interactions.
In this project, we are aiming at characterizing the interactions occurring with the CLL immunoglobulin receptor that are likely responsible for the clinical-biological behavior of subsets of CLL cases expressing stereotyped BCRs. The specific aims are two-fold: 1) to decipher the nature and identity of the antigen(s) binding to stereotyped receptors, and 2) to characterize the structure of the leukemic stereotyped receptors. Both aims will concur to provide crucial information that will integrate in order to achieve targeted therapeutic strategies for each particular subset of the disease.
The definition of the nature and identity of the binding elements to the leukemic BCR combined with the knowledge about the actual structure of the receptor, will be instrumental to find natural ligands or design compounds that might be used to target CLL cells with therapeutic purposes, either by blocking crucial survival stimuli or by directly inducing apoptosis, or by delivering cytotoxic agents.
The proposed project will take advantage of: a) a multi-disciplinary approach, through the integration of the different yet complementary professional expertise at the two partner institutions, including basic immunology, hematology, biophysics, structural biology and bioinformatics; b) a European based collection of cases with “stereotyped” BCRs, the largest of its kind worldwide, developed as part of a long-standing established co-operative effort which was pioneered by the proponents of research. The integration of research efforts in a way capable of providing a new perspective and added-value to existing infrastructure will allow the proponents of research to make important steps towards obtaining a wider, biologically and clinically relevant, picture of the disease.