Research Groups

Molecular Hematology

Research Interests and Description

Group Leader: Dimitar Efremov, MD, PhD

Group Members
Montertondo Outstation

Research Interests

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

Description of Research

The proliferation, differentiation and survival of normal and malignant B-lymphocytes is regulated by intracellular signaling pathways that are activated by signals from the microenvironment. The main interest of the Group concerns the role of these signaling pathways in lymphomagenesis.
Current research focuses primarily on defining and characterizing the B-cell receptor (BCR) signaling 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 B-cell receptor, 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 and MEK/ERK pathways. The role of these pathways in controlling leukemic cell survival, proliferation and expression of relevant apoptosis and cell cycle regulatory proteins is investigated in clinical, in vitro and transgenic mouse models. 
Another goal is to understand the relative contribution of the homologous Syk and ZAP-70 kinases in the initial propagation of the BCR signal. We are focusing especially on the cellular regulatory pathways that are activated by Syk, since this kinase was recently found to be constitutively active in several B-cell malignancies, including CLL. In addition, in vitro and animal studies with specific kinase inhibitors are in progress to determine whether inhibition of antigen-dependent and antigen-independent Syk signaling can be used for targeted therapy of CLL and other B-cell malignancies.

Recent Publications

Bomben, R., Dal Bo, M., Capello, D., Forconi, F., Maffei, R., Laurenti, L., Rossi, D., Del Principe, M.I., Zucchetto, A., Bertoni, F., Rossi, F.M., Bulian, P., Cattarossi, I., Ilariucci, F., Sozzi, E., Spina, V., Zucca, E., Degan, M., Lauria, F., Del Poeta, G., Efremov, D.G., Marasca, R., Gaidano, G., Gattei V. 2009. Molecular and clinical features of chronic lymphocytic leukaemia with stereotyped B cell receptors: results from an Italian multicentre study.  Br. J. Haematol. 144, 492-506

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. doi:10.1016/j.cellsig.2009.03.007

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 leukemia B-cells. Leukemia. 23, 686-697

Tolusso, B., De Santis, M., Bosello, S., Gremese, E., Gobessi, S., Cuoghi, I., Totaro, M.C., Bigotti, G., Rumi, C., Efremov, D.G., Ferraccioli, G. 2009. Synovial B cells of Rheumatoid Arthritis express ZAP-70 which increases the survival and correlates with the inflammatory and autoimmune phenotype. Clin. Immunol. 131, 98-108

Laurenti, L., Tarnani, M., De Padua, L., Efremov, D.G., Zini, G., Garzia, M., Piccirillo, N., Chiusolo, P., Sorà, F., Innocenti, I., Sica, S., Leone, G. 2008. Oral fludarabine and cyclophosphamide as front-line chemotherapy in patients with chronic lymphocytic leukemia. The impact of biological parameters in the response duration. Ann. Hematol. 87, 891-898

Laurenti, L., Tarnani, M., Innocenti, I., Savino, G., Battendieri, R., Larocca, L.M., Chiusolo, P., Sorà, F., Sica, S., Efremov, D., Leone G. Chronic Lymphocytic Leukemia With Eyelid Involvement Responding to Alemtuzumab. 2008. J. Clin. Oncol. 26, 5299-5301

Longo, P.G., Laurenti, L., Gobessi, S., Sica, S., Leone, G., Efremov, D.G. 2008. The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B-cells. Blood. 111, 846-855