Abnormal regulation of BCR signalling by c-Cbl in chronic lymphocytic leukaemia

// Veronica Martini 1, 2 , Federica Frezzato 1, 2 , Filippo Severin 1, 2 , Flavia Raggi 1, 2 , Valentina Trimarco 1, 2 , Leonardo Martinello 1, 2 , Rosa Molfetta 3 , Andrea Visentin 1, 2 , Monica Facco 1, 2 , Gianpietro Semenzato 1, 2 , Rossella Paolini 3 and Livio Trentin 1, 2 1 Department of Medicine, Hematology and Clinical Immunology Branch, University School of Medicine, Padua, Italy 2 Venetian Institute of Molecular Medicine, VIMM, Padua, Italy 3 Department of Molecular Medicine, University of La Sapienza, Rome, Italy Correspondence to: Livio Trentin, email: livio.trentin@unipd.it Keywords: CIN85; Lyn; PI3Kp85; cortactin Abbreviations: BCR: B-Cell Receptor; c-Cbl: c-Casitas B lineage lymphoma; CLL: Chronic Lymphocytic Leukemia Received: May 02, 2018      Accepted: July 21, 2018      Published: August 14, 2018 ABSTRACT Abnormalities of molecules involved in signal transduction pathways are connected to Chronic Lymphocytic Leukemia (CLL) pathogenesis and a critical role has been already ascribed to B-Cell Receptor (BCR)-Lyn axis. E3 ubiquitin ligase c-Cbl, working together with adapter protein CIN85, controls the degradation of protein kinases involved in BCR signaling. To investigate cell homeostasis in CLL, we studied c-Cbl since in normal B cells it is involved in the ubiquitin-dependent Lyn degradation and in the down-regulation of BCR signaling. We found that c-Cbl is overexpressed and not ubiquitinated after BCR engagement. We observed that c-Cbl did not associate to CIN85 in CLL with respect to normal B cells at steady state, nor following BCR engagement. c-Cbl association to Lyn was not detectable in CLL after BCR stimulation, as it happens in normal B cells. In some CLL patients, c-Cbl is constitutively phosphorylated at Y731 and in the same subjects, it associated to regulatory subunit p85 of PI3K. Moreover, c-Cbl is constitutive associated to Cortactin in those CLL patients presenting Cortactin overexpression and bad prognosis. These results support the hypothesis that c-Cbl, rather than E3 ligase activity, could have an adaptor function in turn influencing cell homeostasis in CLL.