Research Papers:

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

Veronica Martini, Federica Frezzato, Filippo Severin, Flavia Raggi, Valentina Trimarco, Leonardo Martinello, Rosa Molfetta, Andrea Visentin, Monica Facco, Gianpietro Semenzato, Rossella Paolini and Livio Trentin _

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Oncotarget. 2018; 9:32219-32231. https://doi.org/10.18632/oncotarget.25951

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Veronica Martini1,2, Federica Frezzato1,2, Filippo Severin1,2, Flavia Raggi1,2, Valentina Trimarco1,2, Leonardo Martinello1,2, Rosa Molfetta3, Andrea Visentin1,2, Monica Facco1,2, Gianpietro Semenzato1,2, Rossella Paolini3 and Livio Trentin1,2

1Department of Medicine, Hematology and Clinical Immunology Branch, University School of Medicine, Padua, Italy

2Venetian Institute of Molecular Medicine, VIMM, Padua, Italy

3Department of Molecular Medicine, University of La Sapienza, Rome, Italy

Correspondence to:

Livio Trentin, email: [email protected]

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


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.

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