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.
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. 2019. Inhibition of SYK or BTK augments venetoclax sensitivity in SHP1-negative/BCL-2-positive diffuse large B-cell lymphoma. Leukemia doi: 10.1038/s41375-019-0442-8. [Epub ahead of print] PubMed link
Efremov, D.G. 2016. IL-4 regulates B-cell receptor signaling in CLL. Blood 128, 468-469 PubMed link
Bojarczuk, K., Sasi, B.K., Gobessi, S., Innocenti, I., Pozzato, G., Laurenti, L., Efremov, D.G. 2016. BCR signaling inhibitors differ in their ability to overcome Mcl-1-mediated resistance of CLL B cells to ABT-199. Blood 127, 3192-201 PubMed link
Iacovelli. S,, Hug, E., Bennardo, S., Duehren-von Minden, M., Gobessi, S., Rinaldi, A., Suljagic, M., Bilbao, D., Bolasco, G., Eckl-Dorna, J., Niederberger, V., Autore, F., Sica, S., Laurenti, L., Wang, H., Cornall, R.J., Clarke, S.H., Croce, C.M., Bertoni, F., Jumaa, H., Efremov, D.G. 2015. Two types of BCR interactions are positively selected during leukemia development in the Em-TCL1 transgenic mouse model of CLL. Blood 125, 1578-1588 PubMed link
Efremov D.G., Gobessi, S. 2014. Signal-dependent and signal-independent functions of the B-cell receptor in chronic lymphocytic leukemia. Haematologica 99, 1645-1646 PubMed link
Woyach, J.A., Bojnik, E., Ruppert, A.S., Stefanovski, M.R., Goettl, V.M., Smucker, K.A., Smith, L.L., Dubovsky, J.A., Towns, W.H., Macmurray, J., Harrington, B.K., Davis, M.E., Gobessi, S., Laurenti, L., Chang, B.Y., Buggy, J.J., Efremov, D.G., Byrd, J.C., Johnson, A.J. 2014. Bruton’s tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood 123, 1207-1213 PubMed link