Phospho-proteomic analysis of mantle cell lymphoma cells suggests a pro-survival role of B-cell receptor signaling

Pighi, Chiara; Gu, Ting‐Lei; Dalai, Irene; Barbi, Stefano; Parolini, Claudia; Bertolaso, Anna; Pedron, Serena; Parisi, Alice; Ren, Jianmin; Cecconi, Daniela; Chilosi, Marco; Menestrina, Fabio; Zamò, Alberto

doi:10.1007/s13402-011-0019-7

Cited by 69 publications

(64 citation statements)

References 56 publications

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“…A recent proteomic screen of phosphorylated proteins in MCL cells indicated that proteins connecting the B-cell receptor (BCR) signaling network were among the most abundant proteins found, and active BCR signaling in MCL cells was confirmed by flow cytometry (66). As depicted in Fig.…”

Section: B-cell Receptor Signaling Pathway: Targeting Bruton Tyrosinementioning

confidence: 90%

New Strategies in the Treatment of Mantle Cell Lymphoma

Deng

Lee²,

O’Connor³

2012

Clinical Cancer Research

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Mantle cell lymphoma (MCL) is a rare type of non-Hodgkin lymphoma that traditionally has been thought to possess the poor-risk features of both indolent lymphoma, with its incurability, and aggressive lymphoma, with its ability to proliferate rapidly. Although there is considerable debate as to whether MCL can be cured, a number of retrospective studies are beginning to suggest an improvement in overall survival over the past decade, likely coinciding with the introduction of rituximab, more intensive chemotherapy, and the increasing use of autologous stem cell transplant (ASCT) in first remission. At present, intensive induction chemotherapy regimens consistently produce a response rate of >90%, sometimes even 100% in the first-line setting, and consolidation with ASCT in first remission can improve the complete response rate to 90%. The emergence of a more sophisticated understanding of the underlying pathogenesis, coupled with a host of new agents and targets, has again created new opportunities to improve the care of our patients with MCL. Here, we discuss many of these developments and how they may potentially affect the natural history of this disease. Clin Cancer Res; 18(13); 3499-508. Ó2012 AACR.

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Section: B-cell Receptor Signaling Pathway: Targeting Bruton Tyrosinementioning

confidence: 90%

New Strategies in the Treatment of Mantle Cell Lymphoma

Deng

Lee²,

O’Connor³

2012

Clinical Cancer Research

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“…Amplification and overexpression of the spleen tyrosine kinase (SYK) and the PI3K catalytic α polypeptide have been found in a subset of MCL (40,41). Furthermore, different kinases of the BCR signaling, including SYK, LYN, and BTK, have been found to be phosphorylated in primary MCL, suggesting activation of the pathway (42).…”

Section: Signaling Pathways Deregulated In MCLmentioning

confidence: 99%

Molecular pathogenesis of mantle cell lymphoma

Jares

Colomer²,

Campo³

2012

J. Clin. Invest.

328

302

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Mantle cell lymphoma is a B cell malignancy in which constitutive dysregulation of cyclin D1 and the cell cycle, disruption of DNA damage response pathways, and activation of cell survival mechanisms contribute to oncogenesis. A small number of tumors lack cyclin D1 overexpression, suggesting that its dysregulation is always not required for tumor initiation. Some cases have hypermutated IGHV and stable karyotypes, a predominant nonnodal disease, and an indolent clinical evolution, which suggests that they may correspond to distinct subtypes of the disease. In this review, we discuss the molecular pathways that contribute to pathogenesis, and how improved understanding of these molecular mechanisms offers new perspectives for the treatment of patients. IntroductionMantle cell lymphoma (MCL) is a B cell malignancy with a broad spectrum of clinical, pathological, and biological features. The identification of the translocation event t(11;14)(q13;q32) and the resulting cyclin D1 overexpression were of paramount importance in recognizing the clinical and biological diversity of this tumor. In addition to this constitutive dysregulation of the cell cycle, other mechanisms such as DNA damage response alterations and activation of cell survival pathways are integrated to drive MCL pathogenesis (1, 2). New observations are expanding our views on the ontogeny and pathogenesis of this lymphoma. Furthermore, these new insights into MCL oncogenesis are promoting the development of new therapeutic strategies, intended to target the molecular mechanism of the disease, and opening up new clinical perspectives for optimal diagnosis and management of the patients.

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“…Once phosphorylated, Lyn and Syk propagate the BCR signal by activating downstream kinases, such as Btk, resulting in the activation of multiple downstream signaling pathways. Recently, it has been reported that MCL cells have constitutive activation of the BCR signal transduction proteins Syk and PKCbII (6,7), as well as high expression of the phosphorylated forms of these and other BCR-associated kinases (8).…”

Section: Introductionmentioning

confidence: 99%

Sorafenib Inhibits Cell Migration and Stroma-Mediated Bortezomib Resistance by Interfering B-cell Receptor Signaling and Protein Translation in Mantle Cell Lymphoma

Xargay-Torrent

López‐Guerra

Montraveta

et al. 2013

Clinical Cancer Research

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Purpose: We evaluated the antitumoral properties of the multikinase inhibitor sorafenib in mantle cell lymphoma (MCL), an aggressive B lymphoma for which current therapies have shown limited efficacy.Experimental Design: Sensitivity to sorafenib was analyzed in MCL cell lines and primary samples in the context of BCR and microenvironment simulation. Sorafenib signaling was characterized by quantitative PCR, Western blotting, immunofluorescence, and protein immunoprecipitation. Migration analysis included flow cytometric counting, actin polymerization assays, and siRNA-mediated knockdown of focal adhesion kinase (FAK). In vivo antitumor effect of sorafenib and bortezomib was analyzed in an MCL xenograft mouse model.Results: Sorafenib rapidly dephosphorylates the BCR-associated kinases, Syk and Lyn, as well as FAK, an Src target involved in focal adhesion. In this line, sorafenib displays strong synergy with the Syk inhibitor, R406. Sorafenib also blocks Mcl-1 and cyclin D1 translation, which promotes an imbalance between proand antiapoptotic proteins and facilitates Bax release from cyclin D1, leading to the induction of mitochondrial apoptosis and caspase-dependent and -independent mechanisms. Moreover, sorafenib inhibits MCL cell migration and CXCL12-induced actin polymerization. FAK knockdown partially prevents this inhibitory effect, indicating that FAK is a relevant target of sorafenib. Furthermore, sorafenib enhances the antitumoral activity of bortezomib in an MCL xenograft mouse model as well as overcomes stromamediated bortezomib resistance in MCL cells.Conclusion: We show for the first time that sorafenib interferes with BCR signaling, protein translation and modulates the microenvironment prosurvival signals in MCL, suggesting that sorafenib, alone or in combination with bortezomib, may represent a promising approach to treat patients with MCL.

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Phospho-proteomic analysis of mantle cell lymphoma cells suggests a pro-survival role of B-cell receptor signaling

Cited by 69 publications

References 56 publications

New Strategies in the Treatment of Mantle Cell Lymphoma

New Strategies in the Treatment of Mantle Cell Lymphoma

Molecular pathogenesis of mantle cell lymphoma

Sorafenib Inhibits Cell Migration and Stroma-Mediated Bortezomib Resistance by Interfering B-cell Receptor Signaling and Protein Translation in Mantle Cell Lymphoma

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