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1.
Leukemia ; 34(1): 100-114, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31197259

RESUMO

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in Toll-like receptor (TLR) signal transduction and innate immune responses. Recruitment and subsequent activation of IRAK4 upon TLR stimulation is mediated by the myeloid differentiation primary response 88 (MYD88) adaptor protein. Around 3% of chronic lymphocytic leukemia (CLL) patients have activating mutations of MYD88, a driver mutation in this disease. Here, we studied the effects of TLR activation and the pharmacological inhibition of IRAK4 with ND2158, an IRAK4 competitive inhibitor, as a therapeutic approach in CLL. Our in vitro studies demonstrated that ND2158 preferentially killed CLL cells in a dose-dependent manner. We further observed a decrease in NF-κB and STAT3 signaling, cytokine secretion, proliferation and migration of primary CLL cells from MYD88-mutated and -unmutated cases. In the Eµ-TCL1 adoptive transfer mouse model of CLL, ND2158 delayed tumor progression and modulated the activity of myeloid and T cells. Our findings show the importance of TLR signaling in CLL development and suggest IRAK4 as a therapeutic target for this disease.

2.
J Exp Clin Cancer Res ; 38(1): 446, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31676012

RESUMO

BACKGROUND: NOTCH1 gene mutations in mantle cell lymphoma (MCL) have been described in about 5-10% of cases and are associated with significantly shorter survival rates. The present study aimed to investigate the biological impact of this mutation in MCL and its potential as a therapeutic target. METHODS: Activation of Notch1 signaling upon ligand-stimulation and inhibitory effects of the monoclonal anti-Notch1 antibody OMP-52M51 in NOTCH1-mutated and -unmutated MCL cells were assessed by Western Blot and gene expression profiling. Effects of OMP-52M51 treatment on tumor cell migration and tumor angiogenesis were evaluated with chemotaxis and HUVEC tube formation assays. The expression of Delta-like ligand 4 (DLL4) in MCL lymph nodes was analyzed by immunofluorescence staining and confocal microscopy. A MCL mouse model was used to assess the activity of OMP-52M51 in vivo. RESULTS: Notch1 expression can be effectively stimulated in NOTCH1-mutated Mino cells by DLL4, whereas in the NOTCH1-unmutated cell line JeKo-1, less effect was observed upon any ligand-stimulation. DLL4 was expressed by histiocytes in both, NOTCH1-mutated and -unmutated MCL lymph nodes. Treatment of NOTCH1-mutated MCL cells with the monoclonal anti-Notch1 antibody OMP-52M51 effectively prevented DLL4-dependent activation of Notch1 and suppressed the induction of numerous direct Notch target genes involved in lymphoid biology, lymphomagenesis and disease progression. Importantly, in lymph nodes from primary MCL cases with NOTCH1/2 mutations, we detected an upregulation of the same gene sets as observed in DLL4-stimulated Mino cells. Furthermore, DLL4 stimulation of NOTCH1-mutated Mino cells enhanced tumor cell migration and angiogenesis, which could be abolished by treatment with OMP-52M51. Importantly, the effects observed were specific for NOTCH1-mutated cells as they did not occur in the NOTCH1-wt cell line JeKo-1. Finally, we confirmed the potential activity of OMP-52M51 to inhibit DLL4-induced Notch1-Signaling in vivo in a xenograft mouse model of MCL. CONCLUSION: DLL4 effectively stimulates Notch1 signaling in NOTCH1-mutated MCL and is expressed by the microenvironment in MCL lymph nodes. Our results indicate that specific inhibition of the Notch1-ligand-receptor interaction might provide a therapeutic alternative for a subset of MCL patients.

3.
Oncogene ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31616059

RESUMO

Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), particularly in NOTCH1-mutated patients. We provide first evidence that the Notch ligand DLL4 is a potent stimulator of Notch signaling in NOTCH1-mutated CLL cells while increases cell proliferation. Importantly, DLL4 is expressed in histiocytes from the lymph node, both in NOTCH1-mutated and -unmutated cases. We also show that the DLL4-induced activation of the Notch signaling pathway can be efficiently blocked with the specific anti-Notch1 antibody OMP-52M51. Accordingly, OMP-52M51 also reverses Notch-induced MYC, CCND1, and NPM1 gene expression as well as cell proliferation in NOTCH1-mutated CLL cells. In addition, DLL4 stimulation triggers the expression of protumor target genes, such as CXCR4, NRARP, and VEGFA, together with an increase in cell migration and angiogenesis. All these events can be antagonized by OMP-52M51. Collectively, our results emphasize the role of DLL4 stimulation in NOTCH1-mutated CLL and confirm the specific therapeutic targeting of Notch1 as a promising approach for this group of poor prognosis CLL patients.

4.
Ann Hematol ; 98(10): 2319-2328, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31396671

RESUMO

Triple-negative primary myelofibrosis (TN-PMF) and other myeloid neoplasms with associated bone marrow fibrosis such as the myelodysplastic syndromes (MDS-F) or the myelodysplastic/myeloproliferative neoplasms (MDS/MPN-F) are rare entities, often difficult to distinguish from each other. Thirty-four patients previously diagnosed with TN-PMF (n = 14), MDS-F (n = 18), or MDS/MPN-F (n = 2) were included in the present study. After central revision of the bone marrow histology, diagnoses according to the 2016-WHO classification were TN-PMF (n = 6), MDS-F (n = 19), and MDS/MPN-F (n = 9), with TN-PMF genotype representing only 4% of a cohort of 141 molecularly annotated PMF. Genomic classification according to next-generation sequencing and cytogenetic study was performed in 28 cases. Median number of mutations was 4 (range 1-7) in cases with TP53 disruption/aneuploidy or with chromatin-spliceosome mutations versus 1 mutation (range 0-2) in other molecular subgroups (p < 0.0001). The number of mutations and the molecular classification were better than PMF and MDS conventional scoring systems to predict survival and progression to acute leukemia. In conclusion, TN-PMF is an uncommon entity when the 2016 WHO criteria are strictly applied. Genomic classification may help in the prognostic assessment of patients with myeloid neoplasms with bone marrow fibrosis.


Assuntos
Neoplasias Hematológicas , Sequenciamento de Nucleotídeos em Larga Escala , Leucemia Mieloide Aguda , Mutação , Síndromes Mielodisplásicas , Mielofibrose Primária , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Neoplasias Hematológicas/classificação , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Humanos , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Mielofibrose Primária/classificação , Mielofibrose Primária/genética , Mielofibrose Primária/mortalidade , Taxa de Sobrevida
5.
Oncol Lett ; 17(6): 5705-5710, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31186796

RESUMO

BCR/ABL1 gene fusion is the hallmark of chronic myeloid leukemia (CML), and is generated in 5-10% of patients by a variant translocation involving 9q34, 22q11.2 and one or more additional genomic regions. The objective of the present study was to characterize, by conventional and molecular cytogenetics, 32 complex variant Philadelphia (Ph) translocations present at diagnosis in patients with CML. The chromosomes most frequently involved were 1 and 5, and the breakpoint most frequently involved was 12p13. The q-chromosome arm was more frequently involved (60%) than the p-arm. The breakpoints were located in the G-light bands in the majority of cases (85%). Additional chromosomal abnormalities were observed in 6 out of 32 (19%) patients. In conclusion, the combination of conventional and molecular cytogenetics studies has allowed us to: i) Detect and quantify the BCR/ABL1 fusion gene; ii) characterize the complex variant translocations and detect cryptic translocations; iii) confirm that the breakpoints are commonly localized in the G-light bands; (iv) confirm that the genesis of variant translocations could be via either the one-step or two-step mechanisms; and v) to report new cases of complex variant translocations.

6.
Int J Cancer ; 144(11): 2762-2773, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30468254

RESUMO

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been shown to be highly effective in patients with chronic lymphocytic leukemia (CLL) and is approved for CLL treatment. Unfortunately, resistance and intolerance to ibrutinib has been observed in several studies, opening the door for more specific BTK inhibitors. CC-292 (spebrutinib) is a BTK inhibitor with increased specificity for BTK and less inhibition of other kinases. Our in vitro studies showed that CC-292 potently inhibited B-cell receptor signaling, activation, proliferation and chemotaxis of CLL cells. In in vivo studies using the adoptive transfer TCL1 mouse model of CLL, CC-292 reduced tumor load and normalized tumor-associated expansion of T cells and monocytes, while not affecting T cell function. Importantly, the combination of CC-292 and bendamustine impaired CLL cell proliferation in vivo and enhanced the control of CLL progression. Our results demonstrate that CC-292 is a specific BTK inhibitor with promising performance in combination with bendamustine in CLL. Further clinical trials are warranted to investigate the therapeutic efficacy of this combination regimen.


Assuntos
Acrilamidas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cloridrato de Bendamustina/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Acrilamidas/uso terapêutico , Adulto , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Medula Óssea/patologia , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Cultura Primária de Células , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas/genética , Pirimidinas/uso terapêutico , Células Tumorais Cultivadas
8.
Haematologica ; 104(3): 576-586, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30262568

RESUMO

Mutations in genes of the RAS-BRAF-MAPK-ERK pathway have not been fully explored in patients with chronic lymphocytic leukemia. We, therefore, analyzed the clinical and biological characteristics of chronic lymphocytic leukemia patients with mutations in this pathway and investigated the in vitro response of primary cells to BRAF and ERK inhibitors. Putative damaging mutations were found in 25 of 452 patients (5.5%). Among these, BRAF was mutated in nine patients (2.0%), genes upstream of BRAF (KITLG, KIT, PTPN11, GNB1, KRAS and NRAS) were mutated in 12 patients (2.6%), and genes downstream of BRAF (MAPK2K1, MAPK2K2, and MAPK1) were mutated in five patients (1.1%). The most frequent mutations were missense, subclonal and mutually exclusive. Patients with these mutations more frequently had increased lactate dehydrogenase levels, high expression of ZAP-70, CD49d, CD38, trisomy 12 and unmutated immunoglobulin heavy-chain variable region genes and had a worse 5-year time to first treatment (hazard ratio 1.8, P=0.025). Gene expression analysis showed upregulation of genes of the MAPK pathway in the group carrying RAS-BRAF-MAPK-ERK pathway mutations. The BRAF inhibitors vemurafenib and dabrafenib were not able to inhibit phosphorylation of ERK, the downstream effector of the pathway, in primary cells. In contrast, ulixertinib, a pan-ERK inhibitor, decreased phospho-ERK levels. In conclusion, although larger series of patients are needed to corroborate these findings, our results suggest that the RAS-BRAF-MAPK-ERK pathway is one of the core cellular processes affected by novel mutations in chronic lymphocytic leukemia, is associated with adverse clinical features and could be pharmacologically inhibited.

9.
J Clin Invest ; 128(9): 4132-4147, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-29990311

RESUMO

Cyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes, and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was proportional to cyclin D1 levels. This cyclin D1-dependent global transcriptional downregulation was associated with a reduced nascent transcription and an accumulation of promoter-proximal paused RNA polymerase II (Pol II) that colocalized with cyclin D1. Concordantly, cyclin D1 overexpression promoted an increase in the Poll II pausing index. This transcriptional impairment seems to be mediated by the interaction of cyclin D1 with the transcription machinery. In addition, cyclin D1 overexpression sensitized cells to transcription inhibitors, revealing a synthetic lethality interaction that was also observed in primary mantle cell lymphoma cases. This finding of global transcriptional dysregulation expands the known functions of oncogenic cyclin D1 and suggests the therapeutic potential of targeting the transcriptional machinery in cyclin D1-overexpressing tumors.


Assuntos
Ciclina D1/genética , Ciclina D1/metabolismo , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Código das Histonas , Humanos , Modelos Biológicos , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética
10.
J Clin Pathol ; 71(11): 975-980, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29934356

RESUMO

AIM: To characterise the clinical and histological features of MPL-mutated essential thrombocythaemia (ET). PATIENTS AND METHODS: Bone marrow biopsies of 175 patients with ET were centrally reviewed according to the 2016 WHO classification, including 42 cases with MPL mutation, 98 JAK2V617F-mutated and 35 CALR-mutated. Clinical and histological features were compared among the three genotypes included in the current 2016 WHO classification and among the different types of MPL mutations. RESULTS: Patients with MPL-mutated ET were significantly older than those with the other genotypes. Haematological values at diagnosis were similar among MPL-mutated and CALR-mutated ET, with both genotypes showing higher platelet counts and lower haemoglobin values than ET with JAK2V617F genotype. In the bone marrow, the median number of megakaryocytes was higher in MPL and CALR than in JAK2V617F genotype (16, 19 and 14 megakaryocytes per ×20 power field, respectively, p=0.004). Histological features of prefibrotic myelofibrosis were rarely observed in MPL genotype, whereas sinusoidal hyperplasia, dense clusters of megakaryocytes and reticulin fibrosis were more frequent in CALR-mutated ET, with 11% of such cases fulfilling WHO 2016 histological criteria of prefibrotic myelofibrosis. With a median follow-up of 3.5 years, no significant differences were seen among genotypes regarding survival, vascular complications or myelofibrotic transformation. There were no significant differences in the clinical data or in the histological characteristics depending on the type of MPL mutation. CONCLUSION: MPL and CALR ET genotypes share clinical and histological characteristics. In contrast to CALR genotype, features of prefibrotic myelofibrosis are uncommon in MPL-mutated ET.


Assuntos
Calreticulina/genética , Janus Quinase 2/genética , Mutação , Mielofibrose Primária/genética , Receptores de Trombopoetina/genética , Trombocitemia Essencial/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Exame de Medula Óssea , Proliferação de Células , Criança , Análise Mutacional de DNA , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Hemoglobinas/análise , Humanos , Masculino , Megacariócitos/patologia , Pessoa de Meia-Idade , Fenótipo , Contagem de Plaquetas , Mielofibrose Primária/sangue , Mielofibrose Primária/patologia , Prognóstico , Trombocitemia Essencial/sangue , Trombocitemia Essencial/patologia , Adulto Jovem
11.
Expert Opin Drug Discov ; 12(10): 1041-1052, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28776453

RESUMO

INTRODUCTION: Next generation sequencing has provided a comprehensive understanding of the mutational landscape in chronic lymphocytic leukemia (CLL), and new drivers have been identified. Some of these drivers could be pharmacologically targeted to choose the most effective personalized therapy in each CLL patient. Areas covered: In this article, the authors uncover the potential role of new targeted therapies against the most recurrent mutations in CLL as well as the recently approved therapies. The authors also provide their expert opinion and give their perspectives for the future. Expert opinion: The development of more personalized therapies is of interest to clinicians as a system to enhance the duration of treatment response and to extend the survival and quality of life of CLL patients. The main challenge, however, will be to translate the preclinical results into the clinics. Therefore, the designing and execution of clinical trials focused on molecular drivers are the need of the hour.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas/métodos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Animais , Desenho de Drogas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Terapia de Alvo Molecular , Mutação , Medicina de Precisão , Qualidade de Vida , Taxa de Sobrevida
13.
Mod Pathol ; 30(5): 745-760, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28084335

RESUMO

Human herpesvirus 8 (HHV8)-associated lymphoid proliferations are uncommon and poorly characterized disorders mainly affecting immunosuppressed patients, especially with HIV infection. They encompass different diseases with overlapping features that complicate their classification. In addition, the role of HHV8 in reactive lymphoid hyperplasia is not well known. To analyze the clinicopathological spectrum of these lesions, we have reviewed 66 biopsies of 61 patients with HHV8 infection. All cases were also investigated for Epstein-Barr virus (EBV) and HIV infection. We identified 13 (20%) cases of HHV8-related reactive lymphoid hyperplasia, 2 (3%) HHV8 plasmablastic proliferations of the splenic red pulp, 28 (42%) multicentric Castleman disease, 6 (9%) germinotropic lymphoproliferative disorders, and 17 (26%) HHV8-related lymphomas. As expected, the pathologic subtype was predictive of overall survival (P<0.05). Forty-seven of our cases were HIV positive (77%). In addition to the classical presentation of the different entities, we identified novel and overlapping features. Reactive HHV8 proliferations were frequently associated with systemic symptoms but never progressed to overt HHV8-positive lymphoma. Two cases had a plasmablastic proliferation limited to spleen. Eight cases of multicentric Castleman disease had a previously unrecognized presentation shortly after the diagnosis of HIV infection, six cases had cavity effusions, and three showed plasmablast enriched proliferations. One germinotropic lymphoproliferative disorder was EBV negative and three occurred in HIV-positive patients, who had distinctive clinical and morphological features. Two of the HHV8-related lymphomas did not fulfill the criteria for previously recognized entities. All these findings expand the clinical and pathological spectrum of HHV8-related lymphoid proliferations, which is broader than current recognized.


Assuntos
Infecções por Herpesviridae/complicações , Herpesvirus Humano 8 , Linfoma/virologia , Transtornos Linfoproliferativos/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Infecções por Herpesviridae/patologia , Humanos , Linfoma/patologia , Transtornos Linfoproliferativos/patologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Oncotarget ; 7(5): 5507-20, 2016 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-26701728

RESUMO

Clinical responses to bendamustine in chronic lymphocytic leukemia (CLL) are highly heterogeneous and no specific markers to predict sensitivity to this drug have been reported. In order to identify biomarkers of response, we analyzed the in vitro activity of bendamustine and the gene expression profile in primary CLL cells. We observed that mRNA expression of CD69 (CD69) and ITGAM (CD11b) constitute the most powerful predictor of response to bendamustine. When we interrogated the predictive value of the corresponding cell surface proteins, the expression of the activation marker CD69 was the most reliable predictor of sensitivity to bendamustine. Importantly, a multivariate analysis revealed that the predictive value of CD69 expression was independent from other clinico-biological CLL features. We also showed that when CLL cells were co-cultured with distinct subtypes of stromal cells, an upregulation of CD69 was accompanied by a reduced sensitivity to bendamustine. In agreement with this, tumor cells derived from lymphoid tumor niches harbored higher CD69 expression and were less sensitive to bendamustine than their peripheral blood counterparts. Furthermore, pretreatment of CD69 high CLL cases with the B-cell receptor (BCR) pathway inhibitors ibrutinib and idelalisib decreased CD69 levels and enhanced bendamustine cytotoxic effect. Collectively, our findings indicate that CD69 could be a predictor of bendamustine response in CLL patients and the combination of clinically-tested BCR signaling inhibitors with bendamustine may represent a promising strategy for bendamustine low responsive CLL cases.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Apoptose/efeitos dos fármacos , Cloridrato de Bendamustina/farmacologia , Lectinas Tipo C/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Purinas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Quinazolinonas/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/genética , Antineoplásicos/farmacologia , Antineoplásicos Alquilantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Feminino , Seguimentos , Humanos , Lectinas Tipo C/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transcriptoma , Células Tumorais Cultivadas
15.
Nature ; 526(7574): 519-24, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26200345

RESUMO

Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.


Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Mutação/genética , Regiões 3' não Traduzidas/genética , Processamento Alternativo/genética , Linfócitos B/metabolismo , Proteínas de Transporte/genética , Cromossomos Humanos Par 9/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , Elementos Facilitadores Genéticos/genética , Genômica , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Fator de Transcrição PAX5/biossíntese , Fator de Transcrição PAX5/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Receptor Notch1/genética , Receptor Notch1/metabolismo , Fatores de Transcrição/genética
16.
Oncotarget ; 6(26): 22734-49, 2015 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-26068951

RESUMO

Mutations or deregulated expression of the components of the spliceosome can influence the splicing pattern of several genes and contribute to the development of tumors. In this context, we report that the spliceosome modulator sudemycin induces selective cytotoxicity in primary chronic lymphocytic leukemia (CLL) cells when compared with healthy lymphocytes and tumor cells from other B-lymphoid malignancies, with a slight bias for CLL cases with mutations in spliceosome-RNA processing machinery. Consistently, sudemycin exhibits considerable antitumor activity in NOD/SCID/IL2Rγ-/- (NSG) mice engrafted with primary cells from CLL patients. The antileukemic effect of sudemycin involves the splicing modulation of several target genes important for tumor survival, both in SF3B1-mutated and -unmutated cases. Thus, the apoptosis induced by this compound is related to the alternative splicing switch of MCL1 toward its proapoptotic isoform. Sudemycin also functionally disturbs NF-κB pathway in parallel with the induction of a spliced RELA variant that loses its DNA binding domain. Importantly, we show an enhanced antitumor effect of sudemycin in combination with ibrutinib that might be related to the modulation of the alternative splicing of the inhibitor of Btk (IBTK). In conclusion, we provide first evidence that the spliceosome is a relevant therapeutic target in CLL, supporting the use of splicing modulators alone or in combination with ibrutinib as a promising approach for the treatment of CLL patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cicloexilaminas/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/farmacologia , Pirimidinas/farmacologia , Compostos de Espiro/farmacologia , Adulto , Idoso , Animais , Cicloexilaminas/administração & dosagem , Sinergismo Farmacológico , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Pessoa de Meia-Idade , Mutação , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Processamento de RNA , Compostos de Espiro/administração & dosagem , Spliceossomos/efeitos dos fármacos , Spliceossomos/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Oncotarget ; 6(25): 21159-72, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26110568

RESUMO

Acadesine is a nucleoside analogue with known activity against B-cell malignancies. Herein, we showed that in mantle cell lymphoma (MCL) cells acadesine induced caspase-dependent apoptosis through turning on the mitochondrial apoptotic machinery. At the molecular level, the compound triggered the activation of the AMPK pathway, consequently modulating known downstream targets, such as mTOR and the cell motility-related vasodilator-stimulated phosphoprotein (VASP). VASP phosphorylation by acadesine was concomitant with a blockade of CXCL12-induced migration. The inhibition of the mTOR cascade by acadesine, committed MCL cells to enter in apoptosis by a translational downregulation of the antiapoptotic Mcl-1 protein. In contrast, Bcl-2 protein levels were unaffected by acadesine and MCL samples expressing high levels of Bcl-2 tended to have a reduced response to the drug. Targeting Bcl-2 with the selective BH3-mimetic agent ABT-199 sensitized Bcl-2high MCL cells to acadesine. This effect was validated in vivo, where the combination of both agents displayed a more marked inhibition of tumor outgrowth than each drug alone. These findings support the notions that antiapoptotic proteins of the Bcl-2 family regulate MCL cell sensitivity to acadesine and that the combination of this agent with Bcl-2 inhibitors might be an interesting therapeutic option to treat MCL patients.


Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Moléculas de Adesão Celular/metabolismo , Linfoma de Célula do Manto/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ribonucleosídeos/administração & dosagem , Sulfonamidas/administração & dosagem , Actinas/química , Aminoimidazol Carboxamida/administração & dosagem , Animais , Apoptose , Linhagem Celular Tumoral/efeitos dos fármacos , Movimento Celular , Quimiocina CXCL12/metabolismo , Quimiotaxia , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos SCID , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Transplante de Neoplasias
18.
Cancer Discov ; 4(12): 1374-6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25477106

RESUMO

Heinig and colleagues, using the Eµ-Tcl1 mouse model of chronic lymphocytic leukemia (CLL), shed light on the trafficking routes of CLL cells into the protective microenvironmental niches in secondary lymphoid organs. The authors propose a crucial role of the resident follicular dendritic cells for leukemia pathogenesis that is essentially orchestrated by the chemokine receptor CXCR5.


Assuntos
Células Dendríticas Foliculares/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Animais
19.
Oncotarget ; 5(16): 6788-800, 2014 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-25216518

RESUMO

Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. Antitumor activity has been observed with mTOR inhibitors. However, they have shown limited clinical efficacy in relation to drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we have performed a comparative analysis of the mTOR inhibitor everolimus, the pan-PI3K inhibitor NVP-BKM120 and the dual PI3K/mTOR inhibitor NVP-BEZ235 in primary MCL cells. We found NVP-BEZ235 to be more powerful than everolimus or NVP-BKM120 in PI3K/Akt/mTOR signaling inhibition, indicating that targeting the PI3K/Akt/mTOR pathway at multiple levels is likely to be a more effective strategy for the treatment of MCL than single inhibition of these kinases. Among the three drugs, NVP-BEZ235 induced the highest change in gene expression profile. Functional validation demonstrated that NVP-BEZ235 inhibited angiogenesis, migration and tumor invasiveness in MCL cells. NVP-BEZ235 was the only drug able to block IL4 and IL6/STAT3 signaling which compromise the therapeutic effect of chemotherapy in MCL. Our findings support the use of the dual PI3K/mTOR inhibitor NVP-BEZ235 as a promising approach to interfere with the microenvironment-related processes in MCL.


Assuntos
Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Aminopiridinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Quimiocina CXCL12/metabolismo , Everolimo , Células Endoteliais da Veia Umbilical Humana , Humanos , Imidazóis/farmacologia , Interleucina-4/antagonistas & inibidores , Interleucina-4/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Linfoma de Célula do Manto/metabolismo , Morfolinas/farmacologia , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Transcriptoma , Microambiente Tumoral/efeitos dos fármacos
20.
Oncotarget ; 5(3): 726-39, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24519895

RESUMO

Mantle cell lymphoma (MCL) is considered one of the most challenging lymphoma, with limited responses to current therapies. Acadesine, a nucleoside analogue has shown antitumoral effects in different preclinical cancer models as well as in a recent phase I/II clinical trial conducted in patients with chronic lymphocytic leukemia. Here we observed that acadesine exerted a selective antitumoral activity in the majority of MCL cell lines and primary MCL samples, independently of adverse cytogenetic factors. Moreover, acadesine was highly synergistic, both in vitro and in vivo, with the anti-CD20 monoclonal antibody rituximab, commonly used in combination therapy for MCL. Gene expression profiling analysis in harvested tumors suggested that acadesine modulates immune response, actin cytoskeleton organization and metal binding, pointing out a substantial impact on metabolic processes by the nucleoside analog. Rituximab also induced changes on metal binding and immune responses.The combination of both drugs enhanced the gene signature corresponding to each single agent, showing an enrichment of genes involved in inflammation, metabolic stress, apoptosis and proliferation. These effects could be important as aberrant apoptotic and proinflammatory pathways play a significant role in the pathogenesis of MCL. In summary, our results suggest that acadesine exerts a cytotoxic effect in MCL in combination with rituximab, by decreasing the proliferative and survival signatures of the disease, thus supporting the clinical examination of this strategy in MCL patients.


Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Anticorpos Monoclonais Murinos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linfoma de Célula do Manto/tratamento farmacológico , Ribonucleosídeos/farmacologia , Aminoimidazol Carboxamida/administração & dosagem , Aminoimidazol Carboxamida/farmacologia , Animais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/imunologia , Antígenos CD20/imunologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Estudos de Coortes , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Humanos , Camundongos , Camundongos SCID , Distribuição Aleatória , Ribonucleosídeos/administração & dosagem , Rituximab , Ensaios Antitumorais Modelo de Xenoenxerto
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