Research Groups

Molecular Hematology

Research Interests and Description

Research Interests

Lymphoid neoplasms; Signal transduction; B-cell receptor; Toll-like receptors; Targeted therapies

Description of Research

The proliferation, differentiation and survival of normal and malignant B-lymphocytes are regulated by intracellular signalling pathways that are activated by signals from the microenvironment. The main interest of the Molecular Hematology Group concerns the role of these signalling pathways in lymphomagenesis.
Current research focuses primarily on defining and characterizing the B-cell receptor (BCR) signalling pathways that promote the survival and expansion of chronic lymphocytic leukemia (CLL) B-cells. Studies of the immunoglobulin variable region gene repertoire have provided compelling evidence that antigen-stimulation through the BCR plays a crucial role in the pathogenesis of this common disease. Moreover, certain features of the BCR, such as the presence of somatic mutations in the immunoglobulin variable region genes and expression of the protein tyrosine kinase ZAP-70, are major determinants of the clinical course. Previous studies from our lab have shown that sustained engagement of the BCR in CLL B-cells results in increased apoptosis resistance that is associated with prolonged activation of the PI3K/AKT pathway. The role of this pathway in controlling leukemic cell survival, proliferation and expression of relevant apoptosis and cell cycle regulatory proteins is investigated in clinical specimens, cell lines and transgenic mouse models.  
Another goal is to understand the relative contribution of the homologous SYK and ZAP-70 kinases in the propagation of the BCR signal. A transgenic mouse model was recently established to address this question and further define the role of ZAP-70 in the pathogenesis of CLL. In addition, preclinical studies performed in our lab have identified SYK as an important therapeutic target and provided further rationale for clinical testing of strategies to target the BCR signalling pathway in CLL.

Recent Publications

Efremov, D.G., Laurenti, L. 2011. The Syk kinase as a therapeutic target in leukemia and lymphoma. Expert Opin Investig Drugs 20, 623-636 PubMed link

Suljagic, M., Laurenti, L., Tarnani, M., Alam, M., Malek, S.N., Efremov, D.G. 2010. Reduced expression of the tumor suppressor PHLPP1 enhances the antiapoptotic B-cell receptor signal in chronic lymphocytic leukemia B cells. Leukemia 24, 2063-2071 PubMed link

Suljagic, M., Longo, P.G., Bennardo, S., Perlas, E., Leone, G., Laurenti, L., Efremov, D.G. 2010. The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the E{micro}-TCL1 transgenic mouse model of CLL by blocking antigen-dependent B cell receptor signaling. Blood DOI 10.1182/blood-2010-03-275180 PubMed link

Tarnani, M., Laurenti, L., Longo, P.G., Piccirillo, N., Gobessi, S., Mannocci, A., Marietti, S., Sica, S., Leone, G., Efremov, D.G. 2010. The proliferative response to CpG-ODN stimulation predicts PFS, TTT and OS in patients with chronic lymphocytic leukemia. Leuk Res 34, 1189-1194 PubMed link

Carsetti, L., Laurenti, L., Gobessi, S., Longo, P.G., Leone, G., Efremov, D.G. 2009. Phosphorylation of the activation loop tyrosines is required for sustained Syk signaling and growth factor-independent B-cell proliferation. Cell Signal 21, 1187-1194 PubMed link

Gobessi, S., Laurenti, L., Longo, P.G., Carsetti, L., Berno, V., Sica, S., Leone, G., Efremov, D.G. 2009. Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic elukemia B-cells. Leukemia  23, 686-697 PubMed link