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Haematologica ; 104(4): 778-788, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29954928


Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than those of the standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, the combination of IQS-01.01RS and CPI203 decreased tumor burden through MYC and p-AKT downregulation, and enhanced the induction of apoptosis. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for the treatment of this disease.

Sci Rep ; 7(1): 13946, 2017 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-29066743


Mantle cell lymphoma (MCL) is a hematologic neoplasm characterised by the t(11;14)(q13;q32) translocation leading to aberrant cyclin D1 expression. The cell functions of cyclin D1 depend on its partners and/or subcellular distribution, resulting in different oncogenic properties. We observed the accumulation of cyclin D1 in the cytoplasm of a subset of MCL cell lines and primary cells. In primary cells, this cytoplasmic distribution was correlated with a more frequent blastoid phenotype. We performed immunoprecipitation assays and mass spectrometry on enriched cytosolic fractions from two cell lines. The cyclin D1 interactome was found to include several factors involved in adhesion, migration and invasion. We found that the accumulation of cyclin D1 in the cytoplasm was associated with higher levels of migration and invasiveness. We also showed that MCL cells with high cytoplasmic levels of cyclin D1 engrafted more rapidly into the bone marrow, spleen, and brain in immunodeficient mice. Both migration and invasion processes, both in vivo and in vitro, were counteracted by the exportin 1 inhibitor KPT-330, which retains cyclin D1 in the nucleus. Our data reveal a role of cytoplasmic cyclin D1 in the control of MCL cell migration and invasion, and as a true operator of MCL pathogenesis.

Movimento Celular , Ciclina D1/metabolismo , Citoplasma/metabolismo , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Transporte Ativo do Núcleo Celular , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Núcleo Celular/metabolismo , Transformação Celular Neoplásica , Citosol/metabolismo , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Proteômica
Clin Cancer Res ; 20(2): 393-403, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24178620


PURPOSE: Clinical responses to the immmunomodulatory drug lenalidomide have been observed in patients with relapsed/refractory mantle cell lymphoma (MCL), although its mechanism of action remains partially unknown. We investigated whether the expression and subcellular localization of cyclin D1, a major cell-cycle regulator overexpressed in MCL, and the cyclin-dependent kinase inhibitor p27(KIP1), could identify MCL cases sensitive to lenalidomide, and whether the compound could modulate cyclin D1/p27(KIP1) complexes in MCL cells. EXPERIMENTAL DESIGN: MCL primary samples and cell lines were analyzed for subcellular levels of cyclin D1/p27(KIP1) complexes by Western blot, immunohistochemistry, immunoprecipitation, and flow cytometry. Activity of lenalidomide in vitro and its effect on cyclin D1/p27(KIP1) complexes were evaluated by real-time PCR, immunoprecipitation, immunofluorescence, and Western blot. In vivo validation was carried out in a mouse xenograft model of human MCL. RESULTS: We found cyclin D1 and p27(KIP1) to be coordinately expressed in all the MCL samples tested. Immunoprecipitation analyses and siRNA assays suggested a direct role of cyclin D1 in the regulation of p27(KIP1) levels. The nuclear accumulation of both proteins correlated with MCL cell tumorigenicity in vivo, and sensitivity to lenalidomide activity in vitro and in vivo. Lenalidomide mechanism of action relied on cyclin D1 downregulation and disruption of cyclin D1/p27(KIP1) complexes, followed by cytosolic accumulation of p27(KIP1), cell proliferation arrest, apoptosis, and angiogenesis inhibition. CONCLUSIONS: These results highlight a mechanism of action of lenalidomide in MCL cases with increased tumorigenicity in vivo, which is mediated by the dissociation of cyclin D1/p27(KIP1) complexes, and subsequent proliferation blockade and apoptosis induction.

Antineoplásicos/farmacologia , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Linfoma de Célula do Manto/metabolismo , Talidomida/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Ciclina D1/antagonistas & inibidores , Ciclina D1/genética , Inibidor de Quinase Dependente de Ciclina p27/antagonistas & inibidores , Inibidor de Quinase Dependente de Ciclina p27/genética , Modelos Animais de Doenças , Feminino , Expressão Gênica , Xenoenxertos , Humanos , Lenalidomida , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Ligação Proteica/efeitos dos fármacos , Estabilidade Proteica , Talidomida/farmacologia , Carga Tumoral/efeitos dos fármacos
Proc Natl Acad Sci U S A ; 110(45): 18250-5, 2013 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-24145436


Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.

Evolução Clonal/genética , Variação Genética , Genoma Humano/genética , Linfoma de Célula do Manto/genética , Mutação/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Sequência de Bases , Ciclina D1/genética , Estudo de Associação Genômica Ampla , Genômica/métodos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma de Célula do Manto/fisiopatologia , Análise em Microsséries , Dados de Sequência Molecular , Receptor Notch2/genética , Receptor 2 Toll-Like/genética
Blood ; 121(12): 2175-85, 2013 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-23321250


Mantle cell lymphoma (MCL) is one of the most aggressive lymphoid neoplasms whose pathogenesis is not fully understood. The neural transcription factor SOX11 is overexpressed in most MCL but is not detected in other mature B-cell lymphomas or normal lymphoid cells. The specific expression of SOX11 in MCL suggests that it may be an important element in the development of this tumor, but its potential function is not known. Here, we show that SOX11 promotes tumor growth in a MCL-xenotransplant mouse model. Using chromatin immunoprecipitation microarray analysis combined with gene expression profiling upon SOX11 knockdown, we identify target genes and transcriptional programs regulated by SOX11 including the block of mature B-cell differentiation, modulation of cell cycle, apoptosis, and stem cell development. PAX5 emerges as one of the major SOX11 direct targets. SOX11 silencing downregulates PAX5, induces BLIMP1 expression, and promotes the shift from a mature B cell into the initial plasmacytic differentiation phenotype in both primary tumor cells and an in vitro model. Our results suggest that SOX11 contributes to tumor development by altering the terminal B-cell differentiation program of MCL and provide perspectives that may have clinical implications in the diagnosis and design of new therapeutic strategies.

Linfócitos B/fisiologia , Diferenciação Celular/genética , Linfoma de Célula do Manto/genética , Fator de Transcrição PAX5/genética , Fatores de Transcrição SOXC/fisiologia , Animais , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/fisiopatologia , Linfopoese/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Invasividade Neoplásica , Fator de Transcrição PAX5/metabolismo , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Transplante Heterólogo