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1.
Blood ; 135(3): 181-190, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31697802

RESUMO

The genetic background of follicular lymphomas (FLs) diagnosed in advanced clinical stages III/IV, and which are frequently characterized by t(14;18), has been substantially unraveled. Molecular features, as exemplified in the clinicogenetic risk model m7FLIPI, are important tools in risk stratification. In contrast, little information is available concerning localized-stage FL (clinical stages I/II), which accounts for ∼20% of newly diagnosed FL in which the detection rate of t(14;18) is only ∼50%. To investigate the genetic background of localized-stage FL, patient cohorts with advanced-stage FL or localized-stage FL, uniformly treated within phase 3 trials of the German Low-Grade Lymphoma Study Group, were comparatively analyzed. Targeted gene expression (GE) profiling of 184 genes using nCounter technology was performed in 110 localized-stage and 556 advanced-stage FL patients. By penalized Cox regression, a prognostic GE signature could not be identified in patients with advanced-stage FL, consistent with results from global tests and univariate regression. In contrast, it was possible to define robust GE signatures discriminating localized-stage and advanced-stage FL (area under the curve, 0.98) by penalized logistic regression. Of note, 3% of samples harboring an "advanced-stage signature" in the localized-stage cohort exhibited inferior failure-free survival (hazard ratio [HR], 7.1; P = .0003). Likewise, in the advanced-stage cohort, 7% of samples with a "localized-stage signature" had prolonged failure-free survival (HR, 2.3; P = .017) and overall survival (HR, 3.4; P = .072). These data support the concept of a biological difference between localized-stage and advanced-stage FL that might contribute to the superior outcome of localized FL.

2.
Leukemia ; 34(2): 543-552, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31530861

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is a disease with heterogeneous outcome. Stromal signatures have been correlated to survival in DLBCL. Their use, however, is hampered by the lack of assays for formalin-fixed paraffin-embedded material (FFPE). We constructed a lymphoma-associated macrophage interaction signature (LAMIS) interrogating features of the microenvironment using a NanoString assay applicable to FFPE. The clinical impact of the signature could be validated in a cohort of 466 patients enrolled in prospective clinical trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Patients with high expression of the signature (LAMIShigh) had shorter EFS, PFS, and OS. Multivariate analyses revealed independence from IPI factors in EFS (HR 1.7, 95% CI 1.2-2.4, p-value = 0.001), PFS (HR 1.8, 95% CI 1.2-2.5, p-value = 0.001) and OS (HR 1.8, 95% CI 1.3-2.7, p-value = 0.001). Multivariate analyses adjusted for the IPI factors showed the signature to be independent from COO, MYC rearrangements and double expresser status (DE). LAMIShigh and simultaneous DE status characterized a patient subgroup with dismal prognosis and early relapse. Our data underline the importance of the microenvironment in prognosis. Combined analysis of stromal features, the IPI and DE may provide a new rationale for targeted therapy.

3.
Br J Haematol ; 187(5): 627-637, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31407320

RESUMO

Mutations in SOCS1 are frequent in primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma. In the latter, SOCS1 mutations affect the length of the encoded protein (major mutations) and are associated with shorter patient survival. Two independent studies examined the prognostic impact of SOCS1 mutations in diffuse large B-cell lymphoma (DLBCL) and showed differing results. This may be due to the small number of included patients, the heterogeneity of patients' demographics and the distinct treatment schemes in these studies. To overcome the size limitations of these previous studies, we assessed SOCS1 mutations in the RICOVER-60 cohort. The cohort uniformly consists of elderly patients (aged 61-80 years) treated with the CHOP-14 scheme (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisolone at 14-day intervals) with or without an additional rituximab treatment. Patient outcomes were analysed with regard to overall SOCS1 mutation frequency, major and minor mutations and a novel impact-based classifier - against the treatment modalities. Patients harbouring putative pathogenic SOCS1 mutations showed significant reduced overall survival within the CHOP plus rituximab group. Hence, putative pathogenic SOCS1 mutations seem to efface the beneficial effect of the therapeutic CD20 antibody. Comparing published data of whole exome and transcriptome sequencing of a large DLBCL cohort confirmed that predicted deleterious SOCS1 mutations forecast pre-eminent survival in early onset DLBCL.

5.
Nat Commun ; 9(1): 4938, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30498195

RESUMO

Chromatin conformation constitutes a fundamental level of eukaryotic genome regulation. However, our ability to examine its biological function and role in disease is limited by the large amounts of starting material required to perform current experimental approaches. Here, we present Low-C, a Hi-C method for low amounts of input material. By systematically comparing Hi-C libraries made with decreasing amounts of starting material we show that Low-C is highly reproducible and robust to experimental noise. To demonstrate the suitability of Low-C to analyse rare cell populations, we produce Low-C maps from primary B-cells of a diffuse large B-cell lymphoma patient. We detect a common reciprocal translocation t(3;14)(q27;q32) affecting the BCL6 and IGH loci and abundant local structural variation between the patient and healthy B-cells. The ability to study chromatin conformation in primary tissue will be fundamental to fully understand the molecular pathogenesis of diseases and to eventually guide personalised therapeutic strategies.


Assuntos
Cromatina/genética , Linfoma Difuso de Grandes Células B/genética , Linhagem Celular Tumoral , Biologia Computacional , Humanos , Proteínas Proto-Oncogênicas c-bcl-6/genética , Fatores de Transcrição/genética
6.
Blood ; 132(16): 1695-1702, 2018 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-30126979

RESUMO

Duodenal-type follicular lymphoma (DTFL) is a rare and highly indolent follicular lymphoma (FL) variant. It is morphologically and immunophenotypically indistinguishable from typical FL, characterized by restricted involvement of intestinal mucosa, and lacks extraintestinal manifestations. The molecular determinants of this distinct clinical behavior are largely unknown. Thirty-eight diagnostic biopsies from patients with DTFL were evaluated. The 10-year overall survival rate was 100% in clinically evaluable patients (n = 19). We compared the targeted mutation profile of DTFL (n = 31), limited-stage typical FL (LSTFL; n = 17), and advanced-stage typical FL (ASTFL; n = 241). The mutation frequencies of recurrently mutated genes, including CREBBP, TNFRSF14/HVEM, and EZH2 were not significantly different. However, KMT2D was less commonly mutated in DTFL (52%) and LSTFL (24%) as compared with ASTFL (79%). In ASTFL, 41% of KMT2D-mutated cases harbored multiple mutations in KMT2D, as compared with only 12% in LSTFL (P = .019) and 0% in DTFL (P < .0001). Whole exome and targeted sequencing of DTFL revealed high mutation frequencies of EEF1A1 (35%) and HVCN1 (22%). We compared the immune microenvironment gene expression signatures of DTFL (n = 8) and LSTFL (n = 7). DTFL clearly separated from LSTFL by unsupervised, hierarchical clustering of 147 chemokines and cytokines and was enriched for a chronic inflammation signature. In conclusion, the mutational landscape of DTFL is highly related to typical FL. The lower frequency of multiple mutations in KMT2D in DTFL and LSTFL indicates an increasing selection pressure for complete KMT2D loss in ASTFL pathogenesis. The highly dissimilar immune microenvironment of DTFL suggests a central role in the biology of this disease.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genética , Neoplasias Duodenais/imunologia , Inflamação/imunologia , Linfoma Folicular/imunologia , Mutação , Proteínas de Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Citocinas/metabolismo , Análise Mutacional de DNA , Neoplasias Duodenais/genética , Neoplasias Duodenais/patologia , Exoma , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/patologia , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Microambiente Tumoral , Adulto Jovem
7.
Nat Med ; 24(8): 1292, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29955181

RESUMO

In the version of this article originally published, some text above the "Tri-nucleotide sequence motifs" label in Fig. 2a appeared incorrectly. The text was garbled and should have appeared as nucleotide codes.Additionally, the labels on the bars in Fig. 2c were not italicized in the original publication. These are gene symbols, and they should have been italicized.The colored labels above the graphs in Fig. 4b were also erroneously not italicized. These labels represent gene names and loci, and they should have been italicized.

9.
Nat Med ; 24(5): 679-690, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29713087

RESUMO

Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.


Assuntos
Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Variações do Número de Cópias de DNA/genética , Rearranjo Gênico/genética , Genes Neoplásicos , Heterogeneidade Genética , Humanos , Mutação/genética , Taxa de Mutação , Resultado do Tratamento
10.
Blood ; 131(18): 2060-2064, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29475959

RESUMO

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) is a newly defined entity in the latest World Health Organization Classification. Accurate diagnosis would appear to mandate fluorescence in situ hybridization (FISH) for all tumors with diffuse large B-cell lymphoma (DLBCL) morphology. We present the results of FISH, cell-of-origin, and immunohistochemistry (IHC) testing from 1228 DLBCL biopsies from 3 clinical trials and a population-based registry. HGBL-DH/TH made up 7.9% of the DLBCL, confined primarily to the germinal center B-cell-like (GCB; 13.3%) compared with activated B-cell-like (ABC; 1.7%) subtype (P < .001). HGBL-DH/TH with BCL2 rearrangement is a GCB phenomenon with no cases observed in 415 ABC DLBCL. A screening strategy restricting FISH testing to tumors of GCB subtype (by Lymph2Cx or Hans IHC) plus dual protein expression of MYC and BCL2 by IHC could limit testing to 11% to 14% of tumors, with a positive predictive value of 30% to 37%; however, this strategy would miss approximately one-quarter of tumors with HBGL-DH/TH with BCL2 rearrangement and one-third of all HGBL-DH/TH. These results provide accurate estimation of the proportion of HGBL-DH/TH among tumors with DLBCL morphology and allow determination of the impact of various methods available to screen DLBCL tumors for FISH testing.


Assuntos
Rearranjo Gênico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Linhagem Celular Tumoral , Humanos , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Gradação de Tumores
11.
Leuk Lymphoma ; 59(5): 1213-1221, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28838257

RESUMO

The incidence of diffuse large B-cell lymphoma (DLBCL) increases with age being patient age at diagnosis an adverse prognostic factor. However, elderly patients are often underrepresented in common studies. To investigate the effect between age and biological characteristics in DLBCL, we analyzed data of 1534 patients encompassing all adult age groups, enriched for the age ≥75 years. Follicular lymphoma (FL) grade 3B with histopathological characteristics of DLBCLs were included. Gender, centroblastic cytology, FL grade 3B morphology, CD10 expression, and ABC/non-GCB-subtype were significantly associated with age after correction for multiple testing and after adjusting for cohorts. Analysis of a subgroup points towards an association of MYC expression with age. Our data indicate that biological features of DLBCL and FL grade 3B are associated with increasing age among adult patients. The prevalence of the ABC/non-GCB-subtype in elderly patients suggests that therapies targeting this molecular subtype should be specifically explored in this subgroup.


Assuntos
Linfócitos B/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/classificação , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
13.
Int J Cancer ; 141(7): 1381-1388, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28614910

RESUMO

TP53 is mutated in 20-25% of aggressive B-cell lymphoma (B-NHL). To date, no studies have addressed the impact of TP53 mutations in prospective clinical trial cohorts. To evaluate the impact of TP53 mutation to current risk models in aggressive B-NHL, we investigated TP53 gene mutations within the RICOVER-60 trial. Of 1,222 elderly patients (aged 61-80 years) enrolled in the study and randomized to six or eight cycles of CHOP-14 with or without Rituximab (NCT00052936), 265 patients were analyzed for TP53 mutations. TP53 mutations were demonstrated in 63 of 265 patients (23.8%). TP53 mutation was associated with higher LDH (65% vs. 37%; p < 0.001), higher international prognostic index-Scores (IPI 4/5 27% vs. 12%; p = 0.025) and B-symptoms (41% vs. 24%; p = 0.011). Patients with TP53 mutation were less likely to obtain a complete remission CR/CRu (CR unconfirmed) 61.9% (mut) vs. 79.7% (wt) (p = 0.007). TP53 mutations were associated with decreased event-free (EFS), progression-free (PFS) and overall survival (OS) (median observation time of 40.2 months): the 3 year EFS, PFS and OS were 42% (vs. 60%; p = 0.012), 42% (vs. 67.5%; p < 0.001) and 50% (vs. 76%; p < 0.001) for the TP53 mutation group. In a Cox proportional hazard analysis adjusting for IPI-factors and treatment arms, TP53 mutation was shown to be an independent predictor of EFS (HR 1.5), PFS (HR 2.0) and OS (HR 2.3; p < 0.001). TP53 mutations are independent predictors of survival in untreated patients with aggressive CD20+ lymphoma. TP53 mutations should be considered for risk models in DLBCL and strategies to improve outcome for patients with mutant TP53 must be developed.


Assuntos
Genes p53 , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Mutação , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Humanos , L-Lactato Desidrogenase , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Rituximab/administração & dosagem , Vincristina/administração & dosagem
14.
J Clin Oncol ; 35(22): 2515-2526, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28525305

RESUMO

Purpose To explore the prognostic impact and interdependence of the cell-of-origin (COO) classification, dual expression (DE) of MYC and BCL2 proteins, and MYC, BCL2, and BCL6 translocations in two prospectively randomized clinical trials of patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Overall, 452 formalin-fixed paraffin-embedded samples from two prospective, randomized DLBCL trials (RICOVER-60, prospective, randomized study for patients > 60 years, all IPI groups; and R-MegaCHOEP, prospective, randomized study for patients ≤ 60 years with age-adjusted IPI 2,3) of the German High-Grade Non-Hodgkin Lymphoma Study Group were analyzed with the Lymph2Cx assay for COO classification, with immunohistochemistry for MYC and BCL2, and with fluorescent in situ hybridization for MYC, BCL2, and BCL6 rearrangements. Results COO classification was successful in 414 of 452 samples. No significant differences with respect to COO (activated B-cell [ABC]-like DLBCL v germinal center B-cell [GCB]-like DLBCL) were observed in event-free survival, progression-free survival, and overall survival in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the RICOVER-60 trial. Also, no differences with respect to COO were observed in multivariable analyses adjusted for International Prognostic Index factors in event-free survival (hazard ratio [HR] of ABC-like disease v GCB-like disease, 1.0; 95% CI, 0.6 to 1.6; P = .93), progression-free survival (HR, 1.1; 95% CI, 0.6 to 1.8; P = .82), and overall survival (HR, 1.0; 95% CI, 0.6 to 1.8; P = .96). Similar results were observed in the R-MegaCHOEP trial. In patients treated with R-CHOP, DE status was associated with significantly inferior survival compared with nonDE within the GCB, but not within the ABC subgroup. DE status was associated with significantly inferior outcome compared with patients with ABC-like DLBCL without DE (5-year PFS rate, 39% [95% CI,19% to 59%] v 68% [95% CI, 52% to 85%]; P = .03) and compared with patients with GCB-like DLBCL without DE. When data from patients with nonDE were analyzed separately, the outcome of patients in the ABC subgroup was inferior to that of patients in the GCB subgroup (5-year PFS rate, 68% [95% CI, 52% to 85%] v 85% [95% CI, 74% to 96%]; P = .04). Conclusion COO profiling in two prospective randomized DLBCL trials failed to identify prognostic subgroups, whereas dual expression of MYC and BCL2 was predictive of poor survival. Evaluation of prognostic or predictive biomarkers in the management of DLBCL, such as the COO, within prospective clinical trials will be important in the future.


Assuntos
Linfoma Difuso de Grandes Células B/química , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-myc/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Alemanha , Centro Germinativo/patologia , Humanos , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Rituximab/administração & dosagem , Taxa de Sobrevida , Translocação Genética , Vincristina/administração & dosagem , Adulto Jovem
15.
Blood ; 130(3): 310-322, 2017 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-28202458

RESUMO

Activated B-cell-like (ABC) and germinal center B-cell-like diffuse large B-cell lymphoma (DLBCL) represent the 2 major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these 2 subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) α/δ (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor κB signaling, prompting us to combine AZD8835 with the Bruton's tyrosine kinase inhibitor ibrutinib. This combination was synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively, our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Oxidiazóis/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Tirosina Quinase da Agamaglobulinemia , Animais , Apoptose/efeitos dos fármacos , Combinação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Camundongos , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Especificidade de Órgãos , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Blood ; 129(3): 333-346, 2017 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-27864294

RESUMO

Mantle cell lymphoma (MCL) is a mature B-cell lymphoma characterized by poor clinical outcome. Recent studies revealed the importance of B-cell receptor (BCR) signaling in maintaining MCL survival. However, it remains unclear which role MALT1, an essential component of the CARD11-BCL10-MALT1 complex that links BCR signaling to the NF-κB pathway, plays in the biology of MCL. Here we show that a subset of MCLs is addicted to MALT1, as its inhibition by either RNA or pharmacologic interference induced cytotoxicity both in vitro and in vivo. Gene expression profiling following MALT1 inhibition demonstrated that MALT1 controls an MYC-driven gene expression network predominantly through increasing MYC protein stability. Thus, our analyses identify a previously unappreciated regulatory mechanism of MYC expression. Investigating primary mouse splenocytes, we could demonstrate that MALT1-induced MYC regulation is not restricted to MCL, but represents a common mechanism. MYC itself is pivotal for MCL survival because its downregulation and pharmacologic inhibition induced cytotoxicity in all MCL models. Collectively, these results provide a strong mechanistic rationale to investigate the therapeutic efficacy of targeting the MALT1-MYC axis in MCL patients.


Assuntos
Caspases/metabolismo , Linfoma de Célula do Manto/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores de Antígenos de Linfócitos B/fisiologia , Animais , Caspases/fisiologia , Morte Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Camundongos , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , NF-kappa B/metabolismo , Proteínas de Neoplasias/fisiologia , Transdução de Sinais
17.
Leuk Lymphoma ; 58(8): 1922-1930, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-27919179

RESUMO

Treatment response of follicular lymphomas (FL) is highly variable. We, therefore, investigated the role of FL cancer-associated fibroblasts (CAFs) on tumor cell viability, in particular in response to treatment with cytotoxic drugs. Stromal cells outgrown from FL patients were characterized and pure CAF populations were co-cultivated with FL cells. To analyze fibroblast-mediated effects, cells in co-culture were treated with ABT-737 and Bortezomib. The adherent cell population was positive for all fibroblastic markers tested and showed increased mRNA-expression of the activation marker FAP. No effect on FL cell viability was noted when co-cultivating them with CAFs. However, stromal cells protected tumor cells from apoptosis in response to cytotoxic treatment. This might be explained by mRNA-induction of ABCC1 and ABCG2 and up-regulation of BCL2L1 in FL cells. Our finding of protective mechanisms mediated by CAFs is of pivotal impact for further studies of cytotoxic agents in FL.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antígenos CD19/genética , Antígenos CD19/metabolismo , Antígenos CD20/genética , Antígenos CD20/metabolismo , Biomarcadores , Compostos de Bifenilo/farmacologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Folicular/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Gradação de Tumores , Neprilisina/genética , Neprilisina/metabolismo , Nitrofenóis/farmacologia , Piperazinas/farmacologia , Sulfonamidas/farmacologia , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
18.
Expert Rev Hematol ; 10(1): 39-51, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27918211

RESUMO

INTRODUCTION: Owing to tremendous advances in the understanding of mechanisms involved in the pathogenesis of malignant tumors an emerging field of novel targeted drugs has evolved within the last decade. This is of particular interest also for malignant lymphomas, constituting a heterogeneous tumor category with substantial variation in clinical outcome, ranging from indolent forms that do not require treatment over years to aggressive cases for which an immediate treatment is mandatory. The elucidation of different molecular strategies adopted by malignant cells has led to a profound profiling of tumor-specific features and consequently resulted in the development of new targeted therapies. Areas covered: A review of currently tested tailored approaches, in particular in B-cell lymphomas (B-NHL), ranging from monoclonal antibodies to inhibition of intrinsic and extrinsic effector molecules. These approaches are currently tested in several subtypes of B-NHL both in preclinical studies and in clinical trials and are summarized within this review. Expert commentary: Considering how quickly basic scientific discoveries could meanwhile be transferred to clinical trials and approvals, future perspectives for novel tailored therapeutic strategies are promising.


Assuntos
Antineoplásicos/uso terapêutico , Heterogeneidade Genética , Linfoma/tratamento farmacológico , Linfoma/genética , Terapia de Alvo Molecular , Animais , Antineoplásicos/farmacologia , Terapia Combinada , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Variação Genética , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Linfoma/metabolismo , Linfoma/patologia , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral
19.
Blood ; 128(8): 1112-20, 2016 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-27418643

RESUMO

Follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease. Posttreatment surrogate end points, such as progression of disease within 24 months (POD24) are promising predictors for overall survival (OS) but are of limited clinical value, primarily because they cannot guide up-front treatment decisions. We used the clinical and molecular data from 2 independent cohorts of symptomatic patients in need of first-line immunochemotherapy (151 patients from a German Low-Grade Lymphoma Study Group [GLSG] trial and 107 patients from a population-based registry of the British Columbia Cancer Agency [BCCA]) to validate the predictive utility of POD24, and to evaluate the ability of pretreatment risk models to predict early treatment failure. POD24 occurred in 17% and 23% of evaluable GLSG and BCCA patients, with 5-year OS rates of 41% (vs 91% for those without POD24, P < .0001) and 26% (vs 86%, P < .0001), respectively. The m7-FL International Prognostic Index (m7-FLIPI), a prospective clinicogenetic risk model for failure-free survival, had the highest accuracy to predict POD24 (76% and 77%, respectively) with an odds ratio of 5.82 in GLSG (P = .00031) and 4.76 in BCCA patients (P = .0052). A clinicogenetic risk model specifically designed to predict POD24, the POD24-PI, had the highest sensitivity to predict POD24, but at the expense of a lower specificity. In conclusion, the m7-FLIPI prospectively identifies the smallest subgroup of patients (28% and 22%, respectively) at highest risk of early failure of first-line immunochemotherapy and death, including patients not fulfilling the POD24 criteria, and should be evaluated in prospective trials of precision medicine approaches in FL.


Assuntos
Progressão da Doença , Imunoterapia , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Folicular/imunologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Reprodutibilidade dos Testes , Fatores de Risco , Análise de Sobrevida
20.
Lancet Oncol ; 16(9): 1111-1122, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26256760

RESUMO

BACKGROUND: Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. METHODS: We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5-9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7-7·6). FINDINGS: We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38·29% (95% CI 25·31-57·95) versus 77·21% (95% CI 69·21-86·14) for the low-risk group (hazard ratio [HR] 4·14, 95% CI 2·47-6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95% CI 2·10-6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%, respectively, with a C-index of 0·80 (95% CI 0·71-0·89). In the validation cohort, m7-FLIPI again defined a high-risk group (22%, 24/107) with 5-year failure-free survival of 25·00% (95% CI 12·50-49·99) versus 68·24% (58·84-79·15) in the low-risk group (HR 3·58, 95% CI 2·00-6·42; p<0.0001). The positive predictive value for 5-year failure-free survival was 72% and 68% for negative predictive value, with a C-index of 0·79 (95% CI 0·69-0·89). In the validation cohort, risk stratification by m7-FLIPI outperformed FLIPI alone (HR 2·18, 95% CI 1·21-3·92), and FLIPI combined with ECOG performance status (HR 2·03, 95% CI 1·12-3·67). INTERPRETATION: Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure. FUNDING: Deutsche Krebshilfe, Terry Fox Research Institute.


Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Imunoterapia , Linfoma Folicular/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Murinos/imunologia , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina , Feminino , Humanos , Linfoma Folicular/genética , Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Prednisona/administração & dosagem , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Vincristina/administração & dosagem
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