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1.
Anticancer Res ; 39(8): 4179-4184, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366503

RESUMO

BACKGROUND/AIM: Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), possesses histone N-methyltransferase (HMT) activity and plays an essential role in cancer initiation and development. The aim of the present study was to investigate the potential of Wedelolactone (WL) to inhibit the methylation activity of EZH2. MATERIALS AND METHODS: The mantle cell lymphoma (MCL) cell line, Mino, was treated with WL, while untreated cells were used as control. HMT activity and EZH2 amount were measured in nuclear extracts from WL-treated and control Mino cells. RESULTS: WL was found to target EZH2-mediated histone H3K27 methylation. Along with the inhibition of H3K27 methylation in vitro (IC50=0.3 µM), WL suppressed HMT activity in Mino cells with an IC50 value of 3.2 µM. We detected a reduced amount of EZH2 in Mino cells treated with WL, compared to untreated control cells. CONCLUSION: This is the first study to show that WL induces inhibition of H3K27 methylation via EZH2 modulation and decreases cell proliferation in MCL, in vitro. WL is proposed as a promising agent and a novel epigenetic approach in MCL investigation and treatment.


Assuntos
Cumarínicos/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Código das Histonas/genética , Linfoma de Célula do Manto/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , Histona Metiltransferases/genética , Histona Metiltransferases/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Metilação/efeitos dos fármacos , Complexo Repressor Polycomb 2/genética
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(3): 820-826, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31204938

RESUMO

OBJECTIVE: To investigate the expression of miR-101 and EZH2 in patients with mantle cell lymphoma(MCL) and to analyze its correlation with clinical prognosis of MCL patients. METHODS: RQ-PCR and S-P immunohistochemistry were used to detect the expressions of miR-101 and EZH2 in tissue of MCL patients. CCK-8 was used to assay the effect of miR-100 minics on the proliferation of Jeko-1 and Mino cells; the flow cytometry with Annexin V/PI double staining was used to assay the apoptosis; Western blot was used to assay the effect of miR-101 minics on the expression of EZH2 protein in Jeko-1 and Mino cells. RESULTS: Compared with control group, miR-101 lowly expressed, and EZH2 protein highly expressed in MCL group, with very statistically significant difference(P<0.01).There was negative correlation between miR-101 and EZH2 expression(r=-0.638,P<0.05). The expression of miR-101 and EZH2 significantly correlated with B symptoms, International Prognostic Index(IPI) and Ann Arbor stage, respectively. Survival analysis showed that the overall survival(OS) rate of patients with low expression of miR-101 were significantly lower than that of patients with high miR-101 expression (P=0.0014), the OS rate of patients with EZH2 high expression were significantly lower than that of patients with EZH2 low expression (P=0.0093). The miR-100 minics could inhibit the proliferation of Jeko-1 and Mino cells, and increase the apoptotic rate. The expression of EZH2 protein was markedly suppressed by the miR-100 minics. CONCLUSION: The expression of miR-101 and EZH2 is different in MCL patients with different clinical stage and prognosis. The miR-101 can inhibit the cell proliferation and induce cell apoptosis of mantle cell lymphoma by targeting EZH2.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Linfoma de Célula do Manto , MicroRNAs/genética , Apoptose , Proliferação de Células , Humanos , Linfoma de Célula do Manto/genética , Prognóstico
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(3): 833-838, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31204940

RESUMO

OBJECTIVE: To explore the expression level of PLK1 in mantle cell lymphoma(MCL), and the effect of silencing PLK1 gene by RNA interference on the cell proliferation, apoptosis, and cell cycle. METHODS: S-P immunohistochemistry technique was used to detect the expression of PLK1 in tissues of 42 patients with MCL and 30 patients with reactive proliferative lymphodenitis(RPL), their expression levels were compared and analyzed. The Jeko-1 cells were transfected with lentivirus contaiming PLK-1 shRNA, then the mRNA and protein expression of PLK-1 was detected by real-time guantitative PCR and Western blot nespectively, and the silencing efficacy of PLK-1 shRNA was identificd. The cell proliferation was detected by CCK method, the cell apoptosis was detected by Annexin V/PI double staining, the cell cycle was detected by PI single staining, the changes of apoptosis-related proteins BAX, BCL-2 and Caspase 3 were detected by Western blot. RESULTS: The positive expression rate of PLK-1 in tissue of MCL patients was 66.67%(28/42), which was significanfly higher than 20%(6/30) in tissue of RPL patients (P<0.05). The PLK-1 positive expression correlated with B symptom, IPI score, Ann-Arbor stage(P<0.05). After infection of Jeko-1 cells with lentivirus containing PLK-1 shRNA for 72 hours, the mRNA and protein expressions of PLK-1 were significantly down-regulated(P<0.05), the proliferation rate of cells in group of PLK-1 shRNA was significanly lower than that in control and Neg shRNA groups(P<0.05); the apoptosis rate of cells in PLK-1 shRNA group was (27.42±3.44)%, which was significantly higher than that in control group (1.23±0.42)% and Neg shRNA group (2.07±0.58) % (P<0.05). The cell cycle analysis showed that the cell ratio in G2/M phase of PLK-1 shRNA group was (27.21±3.59) %, which was higher than that in control group (13.28±2.63)% and Neg shRNA group (14.34±2.37) %. The detection of apoptosis-related proteins showed that the expression of BAX was up-regulated, the expression of BCL-2 was down-regnlated and the expression of caspase 3 was up-regulated. CONCLUSION: The PLK-l overexpression appears in tissue of MCL patients. The silencing PLK-1 gene can inhibit the proliferation of Jeko-1 cells, induce the apopotosis of Jeko-1 cells and arrestes cell cycle in G2/M phase.


Assuntos
Proteínas de Ciclo Celular/genética , Linfoma de Célula do Manto , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Linfoma de Célula do Manto/genética , RNA Interferente Pequeno
4.
Medicine (Baltimore) ; 98(22): e15811, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31145313

RESUMO

Immunoglobulin heavy chain variable region (IGHV) gene mutation status is a biomarker for the prognosis of chronic lymphocytic leukemia, whether it is associated with the diagnosis, staging, and prognosis of patients with mantle cell lymphoma (MCL) remains to be determined.The IGHV gene mutations of 52 MCL patients were determined by DNA sequencing and compared with published IGHV germline sequences.DNA sequence alignment of IGHV variable regions with published IGHV germline sequences showed that the coincidence rate was 94% to 100%. Ten cases (21%) were significantly mutated with the rate of 96.9% to 94.0%. The overall survival time of patients was negatively correlated with the degree of IGHV gene mutation. Further survival analysis with log-rank test demonstrated that the patients with significant IGHV gene mutations showed a trend towards poor survival.The mutation rate of the IGHV variant region may be determined to assess the prognosis and overall survival time of MCL patients.


Assuntos
Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/mortalidade , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Feminino , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Análise de Sobrevida
5.
Cancer Biother Radiopharm ; 34(7): 451-458, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31025879

RESUMO

Background: Mantle cell lymphoma (MCL) is associated with poor patient prognosis mainly due to incomplete response to chemotherapy. S-phase kinase-related protein 2 (SKP2) is an oncoprotein that promotes cell cycle progression and proliferation. A recent study revealed that SKP2 is also involved in DNA damage response mechanisms. SKP2 induces activation of the Ataxia-telangiectasia-mutated (ATM) protein kinase by regulating NBS1 ubiquitination. The authors thus hypothesized that SKP2-mediated ATM activation is associated with MCL resistance to cisplatin (DDP). Materials and Methods: DDP-resistant MCL cell lines JeKo-1/DDP and Mino/DDP were established by culturing JeKo-1 and Mino cells, respectively, with increasing concentrations of DDP. Protein expression levels of SKP2, ATM, and phosphorylated ATM (p-ATM) in the cell lines were assessed using western blotting. The extent of NBS1 ubiquitination was determined with immunoprecipitation assays. Cell viability, apoptosis, and DNA damage were analyzed using specific detection kits. Results: JeKo-1/DDP and Mino/DDP cells showed higher levels of SKP2 and p-ATM proteins than JeKo-1 and Mino cells, respectively. SKP2 knockdown resulted in a reduced NBS1 ubiquitination and p-ATM protein level in JeKo-1/DDP cells. Both SKP2 knockdown and treatment with an ATM inhibitor enhanced DDP-induced DNA damage in JeKo-1/DDP cells by decreasing amounts of RAD51 and FANCD2, which are factors responsible for DNA repair. Consequently, both SKP2 knockdown and ATM inhibition increased the sensitivity of JeKo-1/DDP cells to DDP treatment, with a more pronounced effect observed by SKP2 depletion. Conclusion: These results suggest that SKP2 is likely to be a more promising target than ATM in the treatment of DDP-resistant MCL.


Assuntos
Reparo do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Linfoma de Célula do Manto/genética , Proteínas Quinases Associadas a Fase S/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos
6.
Med Sci Monit ; 25: 2599-2608, 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30964854

RESUMO

BACKGROUND Mantle cell lymphoma (MCL) is a high-grade B-cell lymphoma with poor prognosis. Fludarabine is used alone or in combination for relapsed and advanced-stage MCL. The expression of the signal transducer and activator of transcription 5B (STAT5B) gene is associated with tumorigenesis in solid tumors, but its role in MCL remains unknown. The aims of this study were to investigate the role of STAT5B in GRANTA-519 human mantle cell lymphoma cells and drug resistance. MATERIAL AND METHODS GRANTA-519 human mantle cell lymphoma cells were cultured with and without 10 µM fludarabine dephosphorylated 9-ß-D-arabinofuranosyl-2-fluoroadenine, (2-F-araA) or 10 µM 4-hydroperoxycyclophosphamide (4-HC). The MTT assay assessed cell proliferation. Flow cytometry was used to investigate the cell cycle in MCL cells treated with the specific inhibitor of the Akt pathway, LY294002, and assessed cell cycle and cell apoptosis. Western blot was used to detect the expression levels of p-Akt/Akt and STAT5B/p-STAT5B. The gene expression profiles of lymph node (LN)-derived MCL cells were compared with peripheral blood (PB)-derived lymphocytes using bioinformatics and hierarchical cluster analysis. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed to determine the expression of the marker of proliferation Ki-67 (MKI67) gene. RESULTS STAT5B was significantly upregulated in LN-derived MCL cells compared with PB lymphocytes. Increased expression of STAT5B was associated with increased MCL cell proliferation and reduced cell apoptosis and was associated with drug resistance and activation of Akt. CONCLUSIONS STAT5B promoted cell proliferation and drug resistance in human MCL cells by activating the Akt signaling pathway.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT5/genética , Transdução de Sinais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Ativação Enzimática , Regulação Neoplásica da Expressão Gênica , Humanos , Linfonodos/patologia , Linfócitos/metabolismo , Linfoma de Célula do Manto/enzimologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição STAT5/metabolismo
7.
J Cutan Pathol ; 46(7): 538-541, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30957249

RESUMO

Secondary cutaneous involvement by mantle cell lymphoma (MCL), an uncommon aggressive B-cell malignancy, predominantly involves the dermis, with few reports of pannicular involvement. Lymphocytic infiltration of subcutaneous tissue is associated with inflammatory panniculitides and certain T-cell lymphomas, primarily subcutaneous panniculitis-like T-Cell lymphoma (SPTCL), which is characterized by rimming of adipocytes by tumor cells. We report the case of a 69-year-old man with a history of systemic nodal MCL who presented with subcutaneous nodules on his lower extremities after receiving multi-agent chemotherapy. Biopsies showed a dense infiltrate of atypical, mitotically active, monomorphic, medium-sized lymphoid cells in the subcutaneous fat with prominent rimming of the adipocytes by the tumor cells. These features were not morphologically typical of MCL. Immunohistochemistry showed these cells to be CD20+, CD5+ B-cells with strong cyclin D1 expression; fluorescence in situ hybridization (FISH) analysis was positive for t(11;14)(q13;32), confirming the diagnosis of secondary cutaneous involvement of MCL. This represents an exceptional report of cutaneous MCL presenting clinically and histologically with a panniculitis-type pattern and adipocyte rimming, histomorphologically mimicking SPTCL. Noteworthy examples, such as this report, support the practice of utilizing clinical correlation, immunohistochemistry, and/or molecular cytogenetics to confirm the diagnosis of any case suspicious for cutaneous lymphoma.


Assuntos
Linfoma de Célula do Manto , Linfoma de Células T , Paniculite , Neoplasias Cutâneas , Idoso , Antígenos CD20/genética , Antígenos CD20/metabolismo , Linfócitos B/metabolismo , Linfócitos B/patologia , Antígenos CD5/genética , Antígenos CD5/metabolismo , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 11/metabolismo , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 14/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Diagnóstico Diferencial , Humanos , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Masculino , Paniculite/diagnóstico , Paniculite/genética , Paniculite/metabolismo , Paniculite/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Translocação Genética
8.
Am J Hematol ; 94(6): 710-725, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30963600

RESUMO

Unprecedented advances in our understanding of the pathobiology, prognostication, and therapeutic options in mantle cell lymphoma (MCL) have taken place in the last few years. Heterogeneity in the clinical course of MCL-indolent vs aggressive-is further delineated by a correlation with the mutational status of the variable region of immunoglobulin heavy chain, methylation status, and SOX-11 expression. Cyclin-D1 negative MCL, in situ MCL neoplasia, and impact of the karyotype on prognosis are distinguished. Apart from Ki-67% and morphology pattern (classic vs blastoid/pleomorphic), the proliferation gene signature has helped to further refine prognostication. Studies focusing on mutational dynamics and clonal evolution on Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib) and/or Bcl2 antagonists (venetoclax) have further clarified the prognostic impact of somatic mutations in TP53, BIRC3, CDKN2A, MAP3K14, NOTCH2, NSD2, and SMARCA4 genes. In therapy, long-term follow-up on chemo-immunotherapy studies has demonstrated durable remissions in some patients; however, long-term toxicities, especially from second cancers, are a serious concern with chemotherapy. The therapeutic options in MCL are constantly evolving, with dramatic responses from nonchemotherapeutic agents (ibrutinib, acalabrutinib, and venetoclax). Chimeric antigen receptor therapy and combinations of nonchemotherapeutic agents are actively being studied and our focus is shifting toward making the treatment of MCL chemotherapy-free. Still, MCL remains incurable. The following aspects of MCL continue to pose a challenge: disease transformation, role of the cytokine-microenvironmental milieu, incorporation of positron emission tomography-computerized tomography imaging, minimal residual disease in the prognosis, circulating tumor DNA testing for clonal evolution, predicting resistance to BTK inhibitors, and optimal management of patients who progress on BTK/Bcl2 inhibitors. Next-generation clinical trials should incorporate nonchemotherapeutic agents and personalize the treatment based upon the genomic profile of individual patient. Recent advances in the field of MCL are reviewed.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto , Proteínas de Neoplasias/genética , Intervalo Livre de Doença , Humanos , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/mortalidade , Taxa de Sobrevida
11.
Leukemia ; 33(7): 1675-1686, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30664664

RESUMO

p97 is an ATPase that works in concert with histone deacetylase 6 (HDAC6), to facilitate the degradation of misfolded proteins by autophagosomes. p97 has also been implicated in DNA repair and maintaining genomic stability. In this study, we determined the effect of combined inhibition of p97 and HDAC6 activities in mantle cell lymphoma (MCL) cells. We report that treatment with p97 inhibitors induces dose-dependent apoptosis in MCL cells. The p97 inhibitor CB-5083 induces ER stress markers GRP78 and CHOP and results in the accumulation of polyubiquitylated proteins. Co-treatment with CB-5083 and the HDAC6 inhibitor ACY-1215 result in marked downregulation of CDK4, Cyclin D1, and BRCA1 levels without inhibiting autophagic flux. Consequently, treatment with CB-5083 accentuates DNA damage in response to treatment with ACY-1215 resulting in enhanced accumulation of H2AX-γ and synergistic apoptosis. Furthermore, ATM loss severely impairs phosphorylation of 53BP1 following co-treatment with CB-5083 and ACY-1215 in response to gamma irradiation. Finally, co-treatment CB-5083 and ACY-1215 results in reduced tumor volumes and improves survival in Z138C and Jeko-1 xenografts in NSG mice. These observations suggest that combined inhibition of p97 and HDAC6 abrogates resolution of proteotoxic stress and impairs DNA repair mechanisms in MCL cells.


Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Reparo do DNA/efeitos dos fármacos , Sinergismo Farmacológico , Desacetilase 6 de Histona/antagonistas & inibidores , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Proteínas Nucleares/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Apoptose , Autofagia , Proliferação de Células , Dano ao DNA/efeitos dos fármacos , Quimioterapia Combinada , Regulação Neoplásica da Expressão Gênica , Inibidores de Histona Desacetilases/farmacologia , Humanos , Linfoma de Célula do Manto/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Med Sci Monit ; 25: 365-370, 2019 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-30636001

RESUMO

BACKGROUND LINK-A lncRNA acts as an oncogene in triple-negative breast cancer, but its involvement in other diseases is unknown. The present study was performed to investigate the involvement of LINK-A lncRNA in mantle cell lymphoma. MATERIAL AND METHODS Expressions of LINK-A lncRNA and survivin in plasma of patients with mantle cell lymphoma and healthy controls were detected by qRT-PCR and ELISA, respectively. ROC curve analysis was performed to investigate the diagnostic value of LINK-A lncRNA for mantle cell lymphoma. Correlations between plasma level of LINK-A lncRNA and survivin were analyzed by Pearson correlation coefficient. LINK-A lncRNA shRNA and expression vector were transfected into cells of human mantle cell lymphoma cell lines, followed by detection of cell proliferation, cell apoptosis, and survivin expression by cell proliferation assay, cell apoptosis assay, and Western blot analysis, respectively. RESULTS We found that, compared with healthy controls, plasma levels of LINK-A lncRNA and survivin were significantly increased in patients with mantle cell lymphoma. Upregulation of LINK-A lncRNA sensitively distinguished patients with mantle cell lymphoma from healthy controls. Plasma levels of LINK-A lncRNA and survivin were positively correlated in mantle cell lymphoma patients but not in healthy controls. CONCLUSIONS LINK-A lncRNA overexpression promoted cell proliferation, inhibited cell apoptosis, and upregulated survivin expression, while LINK-A lncRNA knockdown had the opposite effect.


Assuntos
Linfoma de Célula do Manto/genética , RNA Longo não Codificante/fisiologia , Survivina/metabolismo , Adulto , Idoso , Apoptose/genética , Grupo com Ancestrais do Continente Asiático/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , China , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/sangue , RNA Longo não Codificante/genética , Curva ROC , Survivina/genética , Transcriptoma/genética , Regulação para Cima
14.
Blood ; 133(4): 306-318, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30530749

RESUMO

The neural transcription factor SOX11 is usually highly expressed in typical mantle cell lymphoma (MCL), but it is absent in the more indolent form of MCL. Despite being an important diagnostic marker for this hard-to-treat malignancy, the mechanisms of aberrant SOX11 expression are largely unknown. Herein, we describe 2 modes of SOX11 regulation by the cell-cycle regulator cyclin D1 (CCND1) and the signal transducer and activator of transcription 3 (STAT3). We found that ectopic expression of CCND1 in multiple human MCL cell lines resulted in increased SOX11 transcription, which correlated with increased acetylated histones H3K9 and H3K14 (H3K9/14Ac). Increased H3K9/14Ac and SOX11 expression was also observed after histone deacetylase 1 (HDAC1) or HDAC2 was depleted by RNA interference or inhibited by the HDAC inhibitor vorinostat. Mechanistically, we showed that CCND1 interacted with and sequestered HDAC1 and HDAC2 from the SOX11 locus, leading to SOX11 upregulation. Interestingly, our data revealed a potential inverse relationship between phosphorylated Y705 STAT3 and SOX11 expression in MCL cell lines, primary tumors, and patient-derived xenografts. Functionally, inactivation of STAT3 by inhibiting the upstream Janus kinase (JAK) 1 or JAK2 or by STAT3 knockdown was found to increase SOX11 expression, whereas interleukin-21 (IL-21)-induced STAT3 activation or overexpression of the constitutively active form of STAT3 decreased SOX11 expression. In addition, targeting SOX11 directly by RNA interference or indirectly by IL-21 treatment induced toxicity in SOX11+ MCL cells. Collectively, we demonstrate the involvement of CCND1 and STAT3 in the regulation of SOX11 expression, providing new insights and therapeutic implications in MCL.


Assuntos
Ciclina D1/metabolismo , Linfoma de Célula do Manto/genética , Fatores de Transcrição SOXC/genética , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatina/metabolismo , Regulação Neoplásica da Expressão Gênica , Loci Gênicos , Células HEK293 , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Histonas/metabolismo , Humanos , Interleucinas/farmacologia , Fosfotirosina/metabolismo , Ligação Proteica , Processamento de Proteína Pós-Traducional , Fatores de Transcrição SOXC/metabolismo , Regulação para Cima/genética
15.
Nat Med ; 25(1): 119-129, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30455436

RESUMO

Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1-p24.3 loss and/or mutations in components of the SWI-SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI-SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Proteínas Cromossômicas não Histona/genética , Resistencia a Medicamentos Antineoplásicos/genética , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Mutação/genética , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Fatores de Transcrição/genética , Fator 3 Ativador da Transcrição/metabolismo , Linhagem Celular Tumoral , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , DNA Tumoral Circulante/genética , Estudos de Coortes , DNA Helicases/metabolismo , Genoma Humano , Humanos , Modelos Biológicos , Proteínas Nucleares/metabolismo , Prognóstico , Fatores de Transcrição/metabolismo , Resultado do Tratamento , Proteína bcl-X/metabolismo
16.
Mol Cancer Ther ; 18(2): 267-277, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30413649

RESUMO

Bruton's tyrosine kinase (BTK) is a key mediator of BCR-dependent cell growth signaling and a clinically effective therapeutic target in mantle cell lymphoma (MCL). The molecular impact of BTK inhibition remains unclear particularly in hematopoietic malignancies. We analyzed the molecular mechanisms of BTK inhibition with the novel inhibitor BGB-3111 (zanubrutinib) in MCL models. The efficacy of BGB-3111 was investigated using growth proliferation/cell viability and apoptosis assays in MCL cell lines and patient-derived xenograft (PDX) MCL cells. The activity and mechanisms of BGB-3111 were further confirmed using a cell line xenograft model, an MCL PDX mouse model, and a human phosphokinase profiler array and reverse phase protein array. Finally, the mechanisms related to resistance to BTK inhibition were analyzed by creating cell lines with low levels of BTK using CRISPR/Cas 9 genome editing. We found that inhibition of BTK leads to suppression of tumor growth, which was mediated via potent suppression of AKT/mTOR, apoptosis, and metabolic stress. Moreover, targeted disruption of the BTK gene in MCL cells resulted in resistance to BTK inhibition and the emergence of novel survival mechanisms. Our studies suggest a general efficacy of BTK inhibition in MCL and potential drug resistance mechanism via alternative signaling pathways.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Linfoma de Célula do Manto/tratamento farmacológico , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Edição de Genes , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma de Célula do Manto/genética , Camundongos , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Biochem Biophys Res Commun ; 508(4): 1067-1073, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30553455

RESUMO

BACKGROUND: Aberrant expression of B7 homologue 3 (B7H3) has been observed in various malignancies. Our previous study demonstrated that knocking down of B7H3 inhibited cell proliferation, invasion and enhanced the therapeutic efficacy of chemotherapy in mantle cell lymphoma (MCL). However, the mechanism regulating of B7H3 expression remains unknown. Here, we present a new regulatory microRNA of B7H3, miR-506, that directly targets B7H3 and may play an inhibitory role in MCL progression. METHODS: The expression of miR-506 and B7H3 was investigated by real-time quantitative PCR (RT-qPCR). B7H3 was confirmed to be a novel direct target gene of miR-506 by a dual-luciferase assay and western blot analysis. MiR-506 overexpression in the Maver and Z138 MCL cell lines was established using lentiviral transduction. Cell counting kit-8, flow cytometry and Transwell assays were used to detect changes in cell proliferation, cycle distribution, migration and invasion, respectively. RESULTS: The RT-qPCR results showed that miR-506 was expressed at a low level, while B7H3 was overexpressed in MCL patients and cell lines. By using a bioinformatics analysis combined with a dual-luciferase assay, we determined that miR-506 could target the 3'-untranslated region (3'-UTR) of B7H3 mRNA. Moreover, miR-506 had a negative regulatory effect on B7H3 expression according to the western blotting and RT-qPCR results. In terms of function, increased expression of miR-506 led to reduced MCL cell proliferation, invasion and migration, caused cell cycle arrested at G0/G1 phase, similar to the effects of B7H3 knockdown. Furthermore, we measured the expression of invasion-related proteins by western blotting and found that miR-506 could reduce MMP-2 and MMP-9 expression in MCL cells. Rescue experiments suggested that the restoration of B7H3 expression in MCL cells reversed the inhibition of proliferation and invasion induced by miRNA-506 overexpression. CONCLUSIONS: Our findings suggest that miR-506 functions as a tumor suppressor miRNA and plays a significant role in inhibiting human MCL cell proliferation and metastasis by suppressing B7H3 expression.


Assuntos
Antígenos B7/metabolismo , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , MicroRNAs/metabolismo , Regiões 3' não Traduzidas/genética , Antígenos B7/genética , Sequência de Bases , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo/genética , Feminino , Fase G1/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fase de Repouso do Ciclo Celular/genética
18.
Blood ; 133(9): 940-951, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30538135

RESUMO

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1- MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclin D1-/D2- MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1-/SOX11+ MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified CCND2 rearrangements in 39 cases (70%) but not CCND3 rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near CCND3 that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1- MCL cases lacked cyclin D rearrangements and showed upregulation of CCNE1 and CCNE2. These cases had blastoid morphology, high genomic complexity, and CDKN2A and RB1 deletions. Both genomic and gene-expression profiles of cyclin D1- MCL cases were indistinguishable from cyclin D1+ MCL. In conclusion, virtually all cyclin D1- MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1-/D2-/D3- MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1- MCL.


Assuntos
Ciclina D2/genética , Ciclina D3/genética , Elementos Facilitadores Genéticos , Rearranjo Gênico , Cadeias Leves de Imunoglobulina/genética , Linfoma de Célula do Manto/genética , Idoso , Ciclina D1/genética , Ciclina D1/metabolismo , Feminino , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Transcrição SOXC/genética , Translocação Genética
19.
Br J Haematol ; 184(4): 616-624, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30095158

RESUMO

Mantle cell lymphoma (MCL) is still considered incurable and the course of the disease is highly variable. Established risk factors include the Mantle Cell Lymphoma International Prognostic Index (MIPI) and the quantification of the proliferation rate of the tumour cells, e.g. by Ki-67 immunohistochemistry. In this study, we aimed to validate the prognostic value of the gene expression-based MCL35 proliferation assay in patient cohorts from randomized trials of the European Mantle Cell Lymphoma Network. Using this assay, we analysed the gene expression proliferation signature in routine diagnostic lymph node specimens from MCL Younger and MCL Elderly trial patients, and the calculated MCL35 score was used to assign MCL patients to low (61%), standard (27%) or high (12%) risk groups with significantly different outcomes. We confirm here in our prospective clinical trial cohort of MCL patients, that the MCL35 assay is strongly prognostic, providing additional information to the Ki-67 index and the MIPI. Thus, this robust assay may assist in making treatment decisions or in devising risk-adapted prospective clinical trials in the future.


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Linfoma de Célula do Manto , Adulto , Idoso , Idoso de 80 Anos ou mais , Europa (Continente) , Feminino , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
20.
Br J Haematol ; 184(2): 223-231, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30203425

RESUMO

Bendamustine is used in combination with rituximab (BR) to treat indolent non-Hodgkin lymphomas (iNHL) and mantle cell lymphoma (MCL). The variability in treatment efficacy and toxicity could be related to single nucleotide polymorphisms (SNPs) in immune response genes. We would like to show a correlation between SNPs and treatment outcome in iNHL and MCL patients receiving BR. We investigated some SNPs that had already been associated with NHL outcome. Samples were genotyped for the IL2 (rs2069762), IL10 (rs1800890, rs10494879), VEGFA (rs3025039), IL8 (rs4073), CFH (rs1065489) and MTHFR (rs1801131) SNPs by allelic discrimination assays. We enrolled 70 patients that received rituximab 375 mg/m2 and bendamustine 90 mg/m2 every 28 days, both as first-line treatment and ≥ second-line regimens. Overall response rate was 97·1% (complete response [CR] rate 73·9%). Treatment toxicity included grade 3-4 neutropenia (24/70 patients), infections (21/70 patients; 1/70 grade 3), skin rash (26/70 patients; 2/70 grade 3). After a median follow-up of 24 months we did find any correlation between the analysed SNPs, CR rate and PFS. However, we demonstrated an association between the SNP in IL2 (rs2069762) and the onset of skin rash (P = 0·0001). Our study suggests a role for cytokine SNPs in bendamustine-related toxicity, which could represent a promising research field.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Erupção por Droga , Interleucina-2 , Linfoma de Célula do Manto , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Erupção por Droga/genética , Erupção por Droga/metabolismo , Erupção por Droga/patologia , Feminino , Seguimentos , Humanos , Interleucina-2/genética , Interleucina-2/metabolismo , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/genética , Neutropenia/metabolismo , Neutropenia/patologia , Rituximab/administração & dosagem , Rituximab/efeitos adversos
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