Forconi, Francesco - University of Southampton

个人简介

Dr Francesco Forconi joined the University of Southampton in 2011 as a Cancer Research UK Senior Lecturer in Haematological Oncology. He graduated in Medicine and completed his specialist training in Haematology at the University of Siena, Italy. After a fellowship at the University of Eastern Piedmont, Italy, he moved to the Tenovus Laboratories at the University of Southampton, where he obtained a DM in Immunology. There he developed his interests in Tumour B-cell Immunology and subsequently completed his PhD. In 2004 he was appointed as Professor Assistant and Consultant in Haematology at the University of Siena Hospital Trust, before moving back to Southampton in 2011.

研究领域

The B-Cell Receptor (BCR) is the functional unit and unique to any normal B-cell. Its characteristics and functions are preserved after transformation and provide insight in the origin and clinical behaviour of the transformed B-cell. The overall research goal of the Haematological Oncology group is to investigate origin and mechanisms of disease of B-cell lymphomas by analysis of the tumour BCR Immunoglobulin (Ig) characteristics and function. The group will focus on Chronic lymphocytic leukaemia (CLL). The variable clinical course of the two major CLL subsets expressing unmutated or mutated Ig genes (U-CLL and M-CLL, respectively) and the dramatic sensitivity of CLL to inhibitors of BCR-signalling associated kinases highlight the central role of the tumour BCR. CLL cells express low levels of surface Ig (sIg) as a reflection of anergy. However individual circulating cells overexpressing bcl2 will survive and variably recover function to eventually migrate to tissue either for repetitive rounds of antigen-mediated proliferation, and possible secondary genetic damages determining further variability in outcome in the functionally recovered CLL cells, or for sustainment of the anergic CLL cells. One of our projects is to investigate the functional complexity within individual CLL clones defined by B-cell receptor (BCR) level dynamics. Surface IgM (sIgM) is down-modulated following engagement but recovery of expression occurs in vitro, and likely in vivo during recirculation. We can readily identify circulating intraclonal subgroups with varying B-cell receptor expression and function in CLL (Coelho et al. Blood, 2013). Aims of this project will be to investigate the phenotypic, functional and molecular features associated with survival/proliferation, migration and immune suppression in each individual CLL subgroups and the dynamics of recirculation between tissues and blood. A second project is to investigate and to target therapeutically the mechanisms of immune suppression in CLL. BCR signalling is likely to contribute to the immunosuppression which is the main cause of morbidity and mortality in CLL. Recent clinical data demonstrate that new inhibitors of BCR-associated kinases reverse immunosuppression in the initial phases of treatment. Our recent data have confirmed that BCR stimulation modulates immunoregulatory properties of CLL cells. This programme will therefore address the hypothesis that BCR signalling is a key determinant of immune suppression in CLL and possibly in other B-cell malignancies. Current specific aims are (i) to investigate the immunoregulatory phenotype of CLL cells in the presence/absence of BCR stimulation; (ii) to characterise functional consequences of BCR stimulation on immunoregulatory properties of CLL cells; (iii) to investigate effects of novel drugs targeted towards BCR-associated kinases in vitro and in vivo; (iv) to determine the clinical significance of immunoregulatory properties. Stimuli will include various forms of anti-Ig ±costimulation (including TLR-ligands/CD40L/IL4). Inhibitors evaluated will include ibrutinib, idelalisib and tamatinib. For in vivo analysis, samples are available from patients treated with ibrutinib or idelalisib, as part of on-going clinical trials co-ordinated via the NCRI HaemOnc CLL and Lymphoma study subgroups. A third project will be to seek the cell of origin of CLL by Ig gene analysis. In U-CLL, there is increased usage of IGHV1-69 gene, often combined to form stereotypic characteristics of the HCDR3, to suggest selection of the leukemic clones. We have already analysed IGHV1-69/IGHJ6 and IGHV1-69/J3 combinations in normal blood B cells and found that a high proportion have stereotypic patterns similar to those described in U-CLL. Phenotypically the IGHV1-69+ve IgM+ normal B cells are naïve and enriched in CD5+ cells, suggesting a restricted sequence repertoire of the B-cells that may transform in CLL. Our future aim will be to further characterize phenotypically and functionally the potential normal counterparts of CLL cells prior to the putative transforming lesion.

近期论文

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IL-10 production by CLL cells is enhanced in the anergic IGHV mutated subset and associates with reduced DNA methylation of the IL10 locus - Drennan, S., D'Avola, A., Gao, Y., Weigel, C., Chrysostomou, E., Steele, A.J., Zenz, T., Plass, C., Johnson, P.W., Williams, A.O., Packham, G., Stevenson, F.K., Oakes, C.C. and Forconi, F. Published:2017Publication:LeukemiaPage Range:1-9doi:10.1038/leu.2016.356PMID:27890932 PI3K[delta] inhibition elicits anti-leukemic effects through Bim-dependent apoptosis - Carter, Matthew, Cox, Kerry, Blakemore, Stuart, Turaj, Anna, Oldham, Robert, Dahal, Lekh, Tannheimer, Stacey, Forconi, Francesco, Packham, Graham and Cragg, Mark Published:2016Publication:LeukemiaPage Range:1-36 PEITC-mediated inhibition of mRNA translation is associated with both inhibition of mTORC1 and increased eIF2alpha phosphorylation in established cell lines and primary human leukemia cells - Yeomans, Alison, Lemm, Elizabeth, Wilmore, Sarah, Cavell, Breeze, Valle-Argos, Beatriz, Krysov, Sergey, Hidalgo, Marina, Leonard, Elodie, Willis, Anne E., Forconi, Francesco, Stevenson, Freda, Steele, Andrew, Coldwell, Mark and Packham, Graham Published:2016Publication:OncotargetPage Range:1-13doi:10.18632/oncotarget.11655PMID:27579538