NON-COMMUNICABLE DISEASES / Cancer
Lymphoid neoplasms; Signal transduction; B-cell receptor; Toll-like receptors; Targeted therapies
Description of Research
The primary research interests of the Molecular Hematology Group are the cellular and molecular mechanisms involved in the pathogenesis of B cell malignancies and the development of novel approaches for targeted therapy of these diseases. The main focus of our research is chronic lymphocytic leukemia (CLL), which is one of the most common B cell malignancies and the most common type of leukemia in adults.
An important characteristic of CLL is its highly variable clinical course and outcome. This variability is closely associated with certain features of the B cell receptor (BCR), such as the mutational status of the immunoglobulin heavy-chain variable region genes and expression of the BCR-associated kinase ZAP-70. These features, along with the aberrant expression of several other molecules involved in BCR signal transduction, suggest a role for BCR signals in the development and progression of the disease. One of the main lines of research of our laboratory in recent years has been the development of novel transgenic and knockout mouse models to study how these features of the BCR pathway influence the development and progression of CLL.
Another major line of research has been the development of strategies for therapeutic targeting of the BCR pathway in CLL and other B cell malignancies. Studies conducted in previous years identified the kinases SYK, PI3K and AKT as key survival molecules downstream of the BCR and provided the rationale for the clinical development of novel drugs that target these molecules in patients with CLL and other B cell malignancies. One of our current goals is to further improve the efficacy of these agents by identification of biomarkers that can predict response to treatment and development of mechanism-based combination regimens. Similar studies are being conducted in diffuse large B cell lymphoma, which is another common B cell malignancy characterized by aberrant activation of the BCR pathway. In addition, we are collaborating on the development of novel drugs that target other pathways of therapeutic interest in B cell malignancies, such as BCL-2 or the Toll-like receptor pathway.
The Group recently discovered that BCR signalling induces both cell cycle promoters and inhibitors. Loss of the cell cycle inhibitors, principally CDKN1A, CDKN2A, CDKN2B, and p53, results in more aggressive CLL. Importantly, the Group also uncovered that loss of these cell cycle regulators is also important in Richter’s syndrome, where the combination of BCR signalling and loss of these cell cycle inhibitors leads to cell proliferation (Chakraborty et al., Blood 2021).
Chakraborty., S, Martines, C., Porro, F., Fortunati, I., Bonato, A., Dimishkovska, M., Piazza, S., Yadav, B.S., Innocenti, I., Fazio, R., Vaisitti, T., Deaglio, S., Zamò, A., Dimovski, A.J., Laurenti, L., Efremov, D.G. B Cell Receptor signaling and genetic lesions in TP53 and CDKN2A/CDKN2B cooperate in Richter Transformation. Blood,2021. 138(12):1053-1066.
Laurenti, L., Efremov, D.G. Therapeutic Targets in Chronic Lymphocytic Leukemia. Cancers (Basel),2020. 12(11):3259.
Vervloessem, T., Sasi, B., Xerxa, E., Karamanou, L., Kale, J., La Rovere, R.M., Chakraborty, S., Sneyers, F., Vogler, M., Economou, A., Laurenti, L., Andrews, D., Efremov, D.G., Bultynck, G. BDA-366, a putative Bcl-2 BH4 domain antagonist, induces apoptosis independently of Bcl-2 in a variety of cancer cell models. Cell Death Dis,2020. 11(9):769
Corbingi, A,, Innocenti, I., Tomasso, A., Pasquale, R., Visentin, A., Varettoni, M., Flospergher, E., Autore, F., Morelli, F., Trentin, L., Reda, G., Efremov, D.G., Laurenti L. Monoclonal gammopathy and serum immunoglobulin levels as prognostic factors in chronic lymphocytic leukaemia. Br J Haematol,2020. 190(6):901-908.
Efremov, D.G., Turkalj, S., Laurenti, L. Mechanisms of B Cell Receptor Activation and Responses to B Cell Receptor Inhibitors in B Cell Malignancies. Cancers (Basel),2020. 12(6):E1396.
Sasi, B.K, Martines, C,. Xerxa, E., Porro, F., Kalkan, H., Fazio, R., Turkalj, S., Bojnik, E., Pyrzynska, B., Stachura, J., Zerrouqi, A., Bobrowicz, M., Winiarska, M., Priebe, V., Bertoni, F., Mansouri, L., Rosenquist, R., Efremov, D.G. Inhibition of SYK or BTK augments venetoclax sensitivity in SHP1-negative/BCL-2-positive diffuse large B-cell lymphoma. Leukemia,2019. 33(10):2416-2428.