Chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL), the most common adult B-cell malignancy in Western countries, is characterized by the accumulation of monoclonal CD5+ B cells with a characteristic immunophenotype in peripheral blood, bone marrow, and lymphoid tissues. The clinical course of the disease is extremely heterogeneous. As a consequence, the individual life-expectancy ranges from a few years to a virtually normal lifespan. Despite the important progress in its therapy, CLL is still considered an incurable disease.
Since 2013, our group has been involved in several pivotal clinical trials that led to the approval of new drugs for CLL therapy. In particular, the PI of the group has been part of the steering committees of some of these trials and has recently been a lead author for one of the approvals of ibrutinib as front-line CLL therapy. In the field of translational research, our group is involved in several projects focused on the characterization of residual leukemic cells, autoimmunity and mechanisms involved in BCR signaling.
Regarding studies on BCR signaling, our group has investigated the role of some molecules that contribute to regulate the B-cell activation such as CD200 and FcγRIIb. Some of these molecules (i.e., CD200) have been incorporated as one of the diagnostic parameters that can be useful to distinguish CLL from other lymphoproliferative disorders. Additionally, we showed that the molecule FcγRIIb is able to reduce the BCR activation in CLL cells through AKT and ERK signal pathways and described the role of SHIP-1 as a potential molecular therapeutic target in this disease. We also demonstrated that the expression of FcγRIIb has also some prognostic implications in the evolution of the disease.
As per MRD, our group has participated in several projects focused on the standardization of cytometry and molecular techniques within the European Research Initiative on CLL. One of the main research areas of interest in our group is the immunophenotypic and molecular characterization of residual leukemic cells after therapy. We set up a protocol aimed at describing the genomic characteristics of the residual leukemic cells. The second part of this project is still ongoing. Additionally, we are also analyzing MRD in sequential samples in peripheral blood, bone marrow and liquid biopsies in patients treated with several targeted therapies by using different techniques (i.e., flow cytometry, high throughput sequencing, changes in the mutational pattern of some genes before and after therapy).We hypothesize that the analysis of cfDNA and exosomes from liquid biopsy samples of patients with CLL may improve the monitoring of MRD status and help to better understand some of the mechanisms implicated in the resistance of CLL to therapy.
Besides, inherent to the disease, CLL patients have a deregulated immune system, which predispose these patients to have disease complications including recurrent infections and autoimmune phenomena. To understand how the immune cells of tumor microenvironment contribute to maintain the survival of leukemic cells is essential in order to design future therapeutic strategies aimed not only at eradicating leukemic cells but also at restoring the immune system. In the last years our group has started some projects aimed at describing the immune status and functional characteristics of B and T cell populations during the evolution of the disease and after therapy with targeted therapies.