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1.
Lancet Oncol ; 25(7): 922-932, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38936379

RESUMO

BACKGROUND: Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan-temozolomide and dasatinib-rapamycin (RIST) in patients with relapsed or refractory neuroblastoma. METHODS: The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1-25 years with high-risk relapsed (defined as recurrence of all stage IV and MYCN amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan-temozolomide (control group) by block randomisation, stratified by MYCN status. We compared RIST (oral rapamycin [loading 3 mg/m2 on day 1, maintenance 1 mg/m2 on days 2-4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m2 per day] and oral temozolomide [150 mg/m2 per day] for 5 days with 2 days off; one course each of rapamycin-dasatinib and irinotecan-temozolomide for four cycles over 8 weeks, then two courses of rapamycin-dasatinib followed by one course of irinotecan-temozolomide for 12 weeks) with irinotecan-temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at ClinicalTrials.gov, NCT01467986, and is closed to accrual. FINDINGS: Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7-8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31-88), the median progression-free survival was 11 months (95% CI 7-17) in the RIST group and 5 months (2-8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified MYCN (n=48) was 6 months (95% CI 4-24) in the RIST group versus 2 months (2-5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified MYCN (n=76) was 14 months (95% CI 9-7) in the RIST group versus 8 months (4-15) in the control group (HR 0·84 [95% CI 0·51-1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST vs 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] vs 41 [68%]), and anaemia (39 [58%] vs 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure). INTERPRETATION: RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting. FUNDING: Deutsche Krebshilfe.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Dasatinibe , Irinotecano , Recidiva Local de Neoplasia , Neuroblastoma , Sirolimo , Temozolomida , Humanos , Temozolomida/administração & dosagem , Temozolomida/uso terapêutico , Irinotecano/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Masculino , Feminino , Neuroblastoma/tratamento farmacológico , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Neuroblastoma/genética , Pré-Escolar , Criança , Dasatinibe/administração & dosagem , Dasatinibe/uso terapêutico , Dasatinibe/efeitos adversos , Adolescente , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Lactente , Adulto , Sirolimo/administração & dosagem , Sirolimo/uso terapêutico , Adulto Jovem , Alemanha , Resistencia a Medicamentos Antineoplásicos , Intervalo Livre de Progressão
2.
Br J Haematol ; 204(6): 2319-2323, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38527954

RESUMO

Pneumocystis jirovecii can cause life-threatening pneumonia (PjP), and patients with haematological malignancies are at high risk of this infection. Prophylactic measures have significantly decreased morbidity and mortality, but there is a paucity of contemporary data on the incidence and clinical course of PjP in well-defined and homogenous patient populations, such as children suffering from acute lymphoblastic leukaemia (ALL). In the multi-international trial AIEOP-BFM ALL2009, PjP was diagnosed in six children (incidence 1/1000) and was associated with insufficient prophylaxis in five of them. Although none of the patients died of PjP, the long-term impact of the infection is unclear.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Pneumocystis carinii , Pneumonia por Pneumocystis , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Criança , Masculino , Feminino , Pré-Escolar , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adolescente , Incidência
3.
Front Pediatr ; 11: 1104655, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36865689

RESUMO

Background: The prevalence of children with life-limiting conditions is rising, and since the amendment of the social insurance code in Germany, palliative home care teams have treated an increasing number of children. These teams provide 24/7 readiness, yet some parents still call the general emergency medical service (EMS) for various reasons. EMS is exposed to complex medical problems in rare diseases. Questions arose about the experiences of EMS and whether they felt prepared for emergencies involving children treated by a palliative care team. Methods: This study used a mixed methods approach to focus on the interface between palliative care and EMS. First, open interviews were conducted, and a questionnaire was developed based on the results. The variables included demographic items and individual experiences with patients. Second, a case report of a child with respiratory insufficiency was presented to assess the spontaneous treatment intentions of EMS providers. Finally, the need, relevant topics, and duration of specific training in palliative care for EMS providers were evaluated. Results: In total, 1,005 EMS providers responded to the questionnaire. The average age was 34.5 years (±10.94SD), 74.6% were male. The average work experience was 11.8 years (±9.7), 21.4% were medical doctors. Experience with a call of a life-threatening emergency involving a child was reported by 61.5% and severe psychological distress during such a call was reported by 60.4%. The equivalent distress frequency for adult patient calls was 38.3%. (p < 0.001). After review of the case report, the EMS respondents suggested invasive treatment options and rapid transport to the hospital. Most (93.7%) respondents welcomed the consideration of special training in pediatric palliative care. This training should include basic information about palliative care, an analysis of cases involving palliatively treated children, an ethical perspective, practical recommendations, and available (24/7) local contact for further guidance and support. Conclusion: Emergencies in pediatric palliatively treated patients were more common than expected. EMS providers perceived the situations as stressful, and there is a need for specific training with practical aspects.

4.
Front Immunol ; 14: 1140592, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36969210

RESUMO

Objective: The pro-inflammatory cytokine interleukin-1ß (IL-1ß) plays a central role in host defense against infections. High systemic IL-1ß levels, however, promote the pathogenesis of inflammatory disorders. Therefore, mechanisms controlling IL-1ß release are of substantial clinical interest. Recently, we identified a cholinergic mechanism inhibiting the ATP-mediated IL-1ß release by human monocytes via nicotinic acetylcholine receptor (nAChR) subunits α7, α9 and/or α10. We also discovered novel nAChR agonists that trigger this inhibitory function in monocytic cells without eliciting ionotropic functions at conventional nAChRs. Here, we investigate the ion flux-independent signaling pathway that links nAChR activation to the inhibition of the ATP-sensitive P2X7 receptor (P2X7R). Methods: Different human and murine mononuclear phagocytes were primed with lipopolysaccharide and stimulated with the P2X7R agonist BzATP in the presence or absence of nAChR agonists, endothelial NO synthase (eNOS) inhibitors, and NO donors. IL-1ß was measured in cell culture supernatants. Patch-clamp and intracellular Ca2+ imaging experiments were performed on HEK cells overexpressing human P2X7R or P2X7R with point mutations at cysteine residues in the cytoplasmic C-terminal domain. Results: The inhibitory effect of nAChR agonists on the BzATP-induced IL-1ß release was reversed in the presence of eNOS inhibitors (L-NIO, L-NAME) as well as in U937 cells after silencing of eNOS expression. In peripheral blood mononuclear leukocytes from eNOS gene-deficient mice, the inhibitory effect of nAChR agonists was absent, suggesting that nAChRs signal via eNOS to inhibit the BzATP-induced IL-1ß release. Moreover, NO donors (SNAP, S-nitroso-N-acetyl-DL-penicillamine; SIN-1) inhibited the BzATP-induced IL-1ß release by mononuclear phagocytes. The BzATP-induced ionotropic activity of the P2X7R was abolished in the presence of SIN-1 in both, Xenopus laevis oocytes and HEK cells over-expressing the human P2X7R. This inhibitory effect of SIN-1 was absent in HEK cells expressing P2X7R, in which C377 was mutated to alanine, indicating the importance of C377 for the regulation of the P2X7R function by protein modification. Conclusion: We provide first evidence that ion flux-independent, metabotropic signaling of monocytic nAChRs involves eNOS activation and P2X7R modification, resulting in an inhibition of ATP signaling and ATP-mediated IL-1ß release. This signaling pathway might be an interesting target for the treatment of inflammatory disorders.


Assuntos
Leucócitos Mononucleares , Receptores Purinérgicos P2X7 , Humanos , Camundongos , Animais , Interleucina-1beta/metabolismo , Leucócitos Mononucleares/metabolismo , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Monócitos/metabolismo , Trifosfato de Adenosina/metabolismo , Óxido Nítrico Sintase/metabolismo
5.
Front Med (Lausanne) ; 10: 1107148, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36844213

RESUMO

Objective: To compare physician and patient assessments of global disease activity in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and to identify associated factors. Methods: Global disease activity scores (0-10 points) were retrospectively analyzed from physicians and patients with AAV at each outpatient visit from 2010 to 2020. We compared the scores and performed a linear regression with a random effects to identify associated factors. Results: Patients (n = 143, 1,291 pairs, 52% female) had a mean 64 (±15) years of age and a mean disease duration of 9 (±7) years. Patients and physicians global disease activity assessments showed a moderate correlation (Pearson R 0.31, CI [0.23-0.52], p < 0.001). Linear regression showed a strong association between the physician-documented disease activity scores and serum CRP levels (ß = 0.22, CI [0.18, 0.28]), disease duration (ß = -0.022, CI [-0.04,-0.01]) and patients' assessment of disease activity (ß = 0.08, CI [0.04, 0.12]). By contrast, patient assessments were strongly associated with the degree of pain (ß = 0.30, CI [0.25, 0.35]), functional limitations in daily living (HAQ, ß = 0.49, CI [0.21, 0.78]) and the global physical well-being (NRS, ß = 0.39, CI [0.32, 0.46]). Conclusion: Patients' and physicians' assessments of disease activity correlated. High CRP levels and disease duration were associated with physician-assessed disease activity scores, while subjective limitations were associated with higher patient-assessed disease activity scores. These findings highlight and support the need to develop and evaluate patient-reported outcomes to assess disease activity in patients diagnosed with AAV.

6.
Nat Commun ; 13(1): 3881, 2022 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-35794096

RESUMO

While survival has improved for Burkitt lymphoma patients, potential differences in outcome between pediatric and adult patients remain unclear. In both age groups, survival remains poor at relapse. Therefore, we conducted a comparative study in a large pediatric cohort, including 191 cases and 97 samples from adults. While TP53 and CCND3 mutation frequencies are not age related, samples from pediatric patients showed a higher frequency of mutations in ID3, DDX3X, ARID1A and SMARCA4, while several genes such as BCL2 and YY1AP1 are almost exclusively mutated in adult patients. An unbiased analysis reveals a transition of the mutational profile between 25 and 40 years of age. Survival analysis in the pediatric cohort confirms that TP53 mutations are significantly associated with higher incidence of relapse (25 ± 4% versus 6 ± 2%, p-value 0.0002). This identifies a promising molecular marker for relapse incidence in pediatric BL which will be used in future clinical trials.


Assuntos
Linfoma de Burkitt , Adulto , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Proteínas de Ciclo Celular/genética , Criança , DNA Helicases/genética , Genes cdc , Humanos , Mutação , Taxa de Mutação , Recidiva Local de Neoplasia/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética
7.
Front Cell Neurosci ; 16: 779081, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35431807

RESUMO

Activation of nicotinic acetylcholine receptors (nAChRs) expressed by innate immune cells can attenuate pro-inflammatory responses. Silent nAChR agonists, which down-modulate inflammation but have little or no ionotropic activity, are of outstanding clinical interest for the prevention and therapy of numerous inflammatory diseases. Here, we compare two silent nAChR agonists, phosphocholine, which is known to interact with nAChR subunits α7, α9, and α10, and pCF3-N,N-diethyl-N'-phenyl-piperazine (pCF3-diEPP), a previously identified α7 nAChR silent agonist, regarding their anti-inflammatory properties and their effects on ionotropic nAChR functions. The lipopolysaccharide (LPS)-induced release of interleukin (IL)-6 by primary murine macrophages was inhibited by pCF3-diEPP, while phosphocholine was ineffective presumably because of instability. In human whole blood cultures pCF3-diEPP inhibited the LPS-induced secretion of IL-6, TNF-α and IL-1ß. The ATP-mediated release of IL-1ß by LPS-primed human peripheral blood mononuclear leukocytes, monocytic THP-1 cells and THP-1-derived M1-like macrophages was reduced by both phosphocholine and femtomolar concentrations of pCF3-diEPP. These effects were sensitive to mecamylamine and to conopeptides RgIA4 and [V11L; V16D]ArIB, suggesting the involvement of nAChR subunits α7, α9 and/or α10. In two-electrode voltage-clamp measurements pCF3-diEPP functioned as a partial agonist and a strong desensitizer of classical human α9 and α9α10 nAChRs. Interestingly, pCF3-diEPP was more effective as an ionotropic agonist at these nAChRs than at α7 nAChR. In conclusion, phosphocholine and pCF3-diEPP are potent agonists at unconventional nAChRs expressed by monocytic and macrophage-like cells. pCF3-diEPP inhibits the LPS-induced release of pro-inflammatory cytokines, while phosphocholine is ineffective. However, both agonists signal via nAChR subunits α7, α9 and/or α10 to efficiently down-modulate the ATP-induced release of IL-1ß. Compared to phosphocholine, pCF3-diEPP is expected to have better pharmacological properties. Thus, low concentrations of pCF3-diEPP may be a therapeutic option for the treatment of inflammatory diseases including trauma-induced sterile inflammation.

8.
Front Pediatr ; 10: 1105609, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36704133

RESUMO

Introduction: Patients under palliative home care have special needs for their end-of-life support, which in general does not automatically include cardiopulmonary resuscitation. However, emergency medical services (EMS) respond to emergencies in children under palliative care that lead to cardiopulmonary resuscitation. To understand the underlying steps of decision-making, this retrospective, cross-sectional, multicenter study aimed to analyze pediatric patients under palliative home care who had been resuscitated. Methods: This study included patients from three spezialized pediatric palliative home care (SHPC) teams. The primary study parameters were the prevalence of cardiopulmonary resuscitation and the decision-making for carrying out pediatric advanced life support (PALS). Further analyses included the causes of cardiac arrest, the type of CPR (basic life support, advanced life support), the patient´s outcome, and involvement of the SHPC in the resuscitation. Descriptive statistical analysis was performed. Results: In total, 880 pediatric patients under palliative home care were included over 8.5 years, of which 17 patients were resuscitated once and two patients twice (overall, 19 events with CPR, 21.6 per 1,000 cases). In 10 of the 19 incidents (52.6%), cardiac arrest occurred suddenly without being predictable. The causes of cardiac arrest varied widely. PALS was performed in 78.9% of the cases by EMS teams. In 12 of 19 events (63.2%) resuscitation was performed on explicit wish of the parents. However, from a medical point of view, only four resuscitation attempts were reasonable. In total 7 of 17 (41.2%) patients survived cardiac arrest with a comparable quality of life. Discussion: Overall, resuscitation attempts were rare events in children under home palliative therapy, but if they occur, EMS are often the primary caregivers. Most resuscitation attempts occurred on explicit wish of the parents independently of the meaningfulness of the medical procedure. Despite the presence of a life-limiting disease, survival with a similar quality was achieved in one third of all resuscitated patients. This study indicates that EMS should be trained for advanced life support in children under home palliative therapy and SHPC should address the scenario of cardiac arrest also in early stages of palliative treatment. These results underline that advance care planning for these children is urgently needed.

9.
Nat Commun ; 10(1): 1459, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30926794

RESUMO

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.


Assuntos
Linfoma de Burkitt/genética , Genoma Humano , Transcriptoma/genética , Adolescente , Processamento Alternativo/genética , Sequência de Aminoácidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Estudos de Coortes , Metilação de DNA/genética , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação INDEL/genética , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fases de Leitura Aberta/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas c-myc/genética , Translocação Genética , Sequenciamento Completo do Genoma
10.
Haematologica ; 102(6): 1091-1098, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28209658

RESUMO

Mature B-cell non-Hodgkin lymphoma is the most common subtype of non-Hodgkin lymphoma in childhood and adolescence. B-cell non-Hodgkin lymphomas are further classified into histological subtypes, with Burkitt lymphoma and Diffuse large B-cell lymphoma being the most common subgroups in pediatric patients. Translocations involving the MYC oncogene are known as relevant but not sufficient for Burkitt lymphoma pathogenesis. Recently published large-scale next-generation sequencing studies unveiled sets of additional recurrently mutated genes in samples of pediatric and adult B-cell non-Hodgkin lymphoma patients. ID3, TCF3 and CCND3 are potential drivers of Burkitt lymphomagenesis. In the study herein, frequency and clinical relevance of mutations in ID3, TCF3 and CCND3 were analyzed within a well-defined cohort of 84 uniformly diagnosed and treated pediatric B-cell non-Hodgkin lymphoma patients of the Berlin-Frankfurt-Münster group. Mutation frequency was 78% (ID3), 13% (TCF3) and 36% (CCND3) in Burkitt lymphoma (including Burkitt leukemia). ID3 and CCND3 mutations were associated with more advanced stages of the disease in MYC rearrangement positive Burkitt lymphoma. In conclusion, ID3-TCF3-CCND3 pathway genes are mutated in more than 88% of MYC-rearranged pediatric B-cell non-Hodgkin lymphoma and the pathway may represent a highly relevant second hit of Burkitt lymphoma pathogenesis, especially in children and adolescents.


Assuntos
Linfoma de Células B/genética , Taxa de Mutação , Transdução de Sinais/genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linfoma de Burkitt/genética , Criança , Ciclina D3/metabolismo , Feminino , Genes myc/genética , Humanos , Proteínas Inibidoras de Diferenciação/metabolismo , Linfoma de Células B/terapia , Masculino , Proteínas de Neoplasias/metabolismo
11.
Haematologica ; 101(11): 1380-1389, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27390358

RESUMO

MicroRNA are well-established players in post-transcriptional gene regulation. However, information on the effects of microRNA deregulation mainly relies on bioinformatic prediction of potential targets, whereas proof of the direct physical microRNA/target messenger RNA interaction is mostly lacking. Within the International Cancer Genome Consortium Project "Determining Molecular Mechanisms in Malignant Lymphoma by Sequencing", we performed miRnome sequencing from 16 Burkitt lymphomas, 19 diffuse large B-cell lymphomas, and 21 follicular lymphomas. Twenty-two miRNA separated Burkitt lymphomas from diffuse large B-cell lymphomas/follicular lymphomas, of which 13 have shown regulation by MYC. Moreover, we found expression of three hitherto unreported microRNA. Additionally, we detected recurrent mutations of hsa-miR-142 in diffuse large B-cell lymphomas and follicular lymphomas, and editing of the hsa-miR-376 cluster, providing evidence for microRNA editing in lymphomagenesis. To interrogate the direct physical interactions of microRNA with messenger RNA, we performed Argonaute-2 photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation experiments. MicroRNA directly targeted 208 messsenger RNA in the Burkitt lymphomas and 328 messenger RNA in the non-Burkitt lymphoma models. This integrative analysis discovered several regulatory pathways of relevance in lymphomagenesis including Ras, PI3K-Akt and MAPK signaling pathways, also recurrently deregulated in lymphomas by mutations. Our dataset reveals that messenger RNA deregulation through microRNA is a highly relevant mechanism in lymphomagenesis.


Assuntos
Linfoma de Células B/genética , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo , Análise de Sequência de RNA/métodos , Adolescente , Linfoma de Burkitt/genética , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Centro Germinativo , Humanos , Lactente , Recém-Nascido , Linfoma Folicular/genética , Linfoma Difuso de Grandes Células B/genética , Masculino , MicroRNAs/genética , Mutação , Edição de RNA
12.
Nat Genet ; 47(11): 1316-1325, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26437030

RESUMO

Although Burkitt lymphomas and follicular lymphomas both have features of germinal center B cells, they are biologically and clinically quite distinct. Here we performed whole-genome bisulfite, genome and transcriptome sequencing in 13 IG-MYC translocation-positive Burkitt lymphoma, nine BCL2 translocation-positive follicular lymphoma and four normal germinal center B cell samples. Comparison of Burkitt and follicular lymphoma samples showed differential methylation of intragenic regions that strongly correlated with expression of associated genes, for example, genes active in germinal center dark-zone and light-zone B cells. Integrative pathway analyses of regions differentially methylated in Burkitt and follicular lymphomas implicated DNA methylation as cooperating with somatic mutation of sphingosine phosphate signaling, as well as the TCF3-ID3 and SWI/SNF complexes, in a large fraction of Burkitt lymphomas. Taken together, our results demonstrate a tight connection between somatic mutation, DNA methylation and transcriptional control in key B cell pathways deregulated differentially in Burkitt lymphoma and other germinal center B cell lymphomas.


Assuntos
Linfoma de Burkitt/genética , Metilação de DNA , Linfoma Folicular/genética , Mutação , Transcriptoma/genética , Adolescente , Adulto , Idoso , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Genoma Humano/genética , Centro Germinativo/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais/genética , Translocação Genética , Adulto Jovem
13.
Proc Natl Acad Sci U S A ; 112(38): E5261-70, 2015 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-26351698

RESUMO

Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long noncoding RNAs (lncRNAs), on MYC ability to influence the cellular transcriptome. Here, we have intersected RNA-sequencing data from two MYC-inducible cell lines and a cohort of 91 B-cell lymphomas with or without genetic variants resulting in MYC overexpression. We identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them, we focused on a lncRNA that we named MYC-induced long noncoding RNA (MINCR), showing a strong correlation with MYC expression in MYC-positive lymphomas. To understand its cellular role, we performed RNAi and found that MINCR knockdown is associated with an impairment in cell cycle progression. Differential gene expression analysis after RNAi showed a significant enrichment of cell cycle genes among the genes down-regulated after MINCR knockdown. Interestingly, these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of the MYC transcriptional program. Accordingly, MINCR knockdown was associated with a reduction in MYC binding to the promoters of selected cell cycle genes. Finally, we show that down-regulation of Aurora kinases A and B and chromatin licensing and DNA replication factor 1 may explain the reduction in cellular proliferation observed on MINCR knockdown. We, therefore, suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.


Assuntos
Linfoma de Burkitt/metabolismo , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Linfoma de Células B/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Longo não Codificante/metabolismo , Sequência de Bases , Sítios de Ligação , Ciclo Celular , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Cromatina/metabolismo , Perfilação da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Dados de Sequência Molecular , Neoplasias/metabolismo , Regiões Promotoras Genéticas , RNA Interferente Pequeno/metabolismo , Homologia de Sequência do Ácido Nucleico
14.
Genes Chromosomes Cancer ; 54(9): 555-64, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26173642

RESUMO

The genetic hallmark of Burkitt lymphoma is the translocation t(8;14)(q24;q32), or one of its light chain variants, resulting in IG-MYC juxtaposition. However, these translocations alone are insufficient to drive lymphomagenesis, which requires additional genetic changes for malignant transformation. Recent studies of Burkitt lymphoma using next generation sequencing approaches have identified various recurrently mutated genes including ID3, TCF3, CCND3, and TP53. Here, by using similar approaches, we show that PCBP1 is a recurrently mutated gene in Burkitt lymphoma. By whole-genome sequencing, we identified somatic mutations in PCBP1 in 3/17 (18%) Burkitt lymphomas. We confirmed the recurrence of PCBP1 mutations by Sanger sequencing in an independent validation cohort, finding mutations in 3/28 (11%) Burkitt lymphomas and in 6/16 (38%) Burkitt lymphoma cell lines. PCBP1 is an intron-less gene encoding the 356 amino acid poly(rC) binding protein 1, which contains three K-Homology (KH) domains and two nuclear localization signals. The mutations predominantly (10/12, 83%) affect the KH III domain, either by complete domain loss or amino acid changes. Thus, these changes are predicted to alter the various functions of PCBP1, including nuclear trafficking and pre-mRNA splicing. Remarkably, all six primary Burkitt lymphomas with a PCBP1 mutation expressed MUM1/IRF4, which is otherwise detected in around 20-40% of Burkitt lymphomas. We conclude that PCBP1 mutations are recurrent in Burkitt lymphomas and might contribute, in cooperation with other mutations, to its pathogenesis.


Assuntos
Linfoma de Burkitt/genética , Ribonucleoproteínas Nucleares Heterogêneas/genética , Mutação , Adolescente , Adulto , Idoso , Linfoma de Burkitt/metabolismo , Linhagem Celular Tumoral , Criança , Pré-Escolar , Estudos de Coortes , Proteínas de Ligação a DNA , Feminino , Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/química , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Masculino , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas de Ligação a RNA , Adulto Jovem
15.
Br J Haematol ; 170(6): 814-25, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26104998

RESUMO

Typical Burkitt lymphoma is characterized by an IG-MYC translocation and overall low genomic complexity. Clinically, Burkitt lymphoma has a favourable prognosis with very few relapses. However, the few patients experiencing disease progression and/or relapse have a dismal outcome. Here we report cytogenetic findings of seven cases of Burkitt lymphoma in which sequential karyotyping was performed at time of diagnosis and/or disease progression/relapse(s). After case selection, karyotype re-review and additional molecular analyses were performed in six paediatric cases, treated in Berlin-Frankfurt-Münster-Non-Hodgkin lymphoma study group trials, and one additional adult patient. Moreover, we analysed 18 cases of Burkitt lymphoma from the Mitelman database in which sequential karyotyping was performed. Our findings show secondary karyotypes to have a significant increase in load of cytogenetic aberrations with a mean number of 2, 5 and 8 aberrations for primary, secondary and third investigations. Importantly, this increase in karyotype complexity seemed to result from recurrent secondary chromosomal changes involving mainly trisomy 21, gains of 1q and 7q, losses of 6q, 11q, 13q, and 17p. In addition, our findings indicate a linear clonal evolution to be the predominant manner of cytogenetic evolution. Our data may provide a biological framework for the dismal outcome of progressive and relapsing Burkitt lymphoma.


Assuntos
Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Aberrações Cromossômicas , Evolução Clonal/genética , Adolescente , Linfoma de Burkitt/diagnóstico , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Genes myc , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Modelos Teóricos , Recidiva Local de Neoplasia , Fatores de Tempo , Translocação Genética
18.
Genes Chromosomes Cancer ; 53(11): 911-6, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25044415

RESUMO

Burkitt lymphoma (BL) is the most frequent B-cell lymphoma in childhood. Genetically, it is characterized by the presence of an IG-MYC translocation which is supposed to be an initiating but not sufficient event in Burkitt lymphomagenesis. In a recent whole-genome sequencing study of four cases, we showed that the gene encoding the ras homolog family member A (RHOA) is recurrently mutated in pediatric BL. Here, we analyzed RHOA by Sanger sequencing in a cohort of 101 pediatric B-cell lymphoma patients treated according to Non-Hodgkin's Lymphoma Berlin-Frankfurt-Münster (NHL-BFM) study protocols. Among the 78 BLs in this series, an additional five had RHOA mutations resulting in a total incidence of 7/82 (8.5%) with c.14G>A (p.R5Q) being present in three cases. Modeling the mutational effect suggests that most of them inactivate the RHOA protein. Thus, deregulation of RHOA by mutation is a recurrent event in Burkitt lymphomagenesis in children.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Burkitt/genética , Linfoma de Células B/genética , Proteína rhoA de Ligação ao GTP/genética , Adolescente , Asparaginase/uso terapêutico , Linfoma de Burkitt/patologia , Linfoma de Burkitt/terapia , Criança , Pré-Escolar , Estudos de Coortes , Daunorrubicina/uso terapêutico , Feminino , Humanos , Linfoma de Células B/patologia , Linfoma de Células B/terapia , Masculino , Mutação , Pediatria , Prednisona/uso terapêutico , Vincristina/uso terapêutico , Proteína rhoA de Ligação ao GTP/metabolismo
19.
Pediatr Hematol Oncol ; 30(6): 465-83, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23570584

RESUMO

Mature B-cell non-Hodgkin lymphoma (B-NHL) comprises more than 50% of all non-Hodgkin lymphoma (NHL) in children and adolescents. Many B-NHL subtypes frequently observed in adults are rarely diagnosed in children and adolescents. In this age group, Burkitt lymphoma (BL), Burkitt leukemia or FAB L3 leukemia (B-AL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMLBL), follicular lymphoma (FL), and aggressive mature B-NHL not further classifiable (B-NHL nfc) are the most common subtypes. Diverse clinical trials demonstrated similar results of current combination chemotherapy regimens succeeding in overall survival rates of more than 80%. However, treatment-related toxicity and the poor prognosis of relapse are serious concerns. Furthermore, specific histological B-NHL subtypes are rare in children and optimal treatment is not established. New treatment modalities are urgently needed for these patient groups. Rituximab, a monoclonal antibody that is already established in the treatment of adults with mature B-NHL, demonstrated promising results in pediatric patients. The definitive role of rituximab in the treatment of children and adolescents with B-NHL needs to be evaluated in prospective controlled clinical trials. This review provides a comprehensive overview of chemotherapy regimens and the perspectives for children and adolescents with mature B-cell lymphoma and leukemia.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/normas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia de Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Adolescente , Adulto , Anticorpos Monoclonais Murinos/uso terapêutico , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Leucemia de Células B/classificação , Leucemia de Células B/mortalidade , Linfoma de Células B/classificação , Linfoma de Células B/mortalidade , Masculino , Estudos Prospectivos , Rituximab , Taxa de Sobrevida
20.
Blood ; 121(16): 3153-60, 2013 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-23396305

RESUMO

Probability of event-free survival (pEFS) in pediatric T-cell lymphoblastic lymphoma is about 80%, whereas survival in relapsed patients is very poor. No stratification criteria have been established so far. Recently, activating NOTCH1 mutations were reported to be associated with favorable prognosis, and loss of heterozygosity at chromosome 6q (LOH6q) was reported to be associated with increased relapse risk. The current project was intended to evaluate the prognostic effect of these markers. Mutations in hot spots of NOTCH1 and FBXW7 were analyzed in 116 patients. Concerning LOH6q status, 118 patients were investigated, using microsatellite marker analysis, in addition to an earlier reported cohort of 99 available patients. Ninety-two cases were evaluable for both analyses. All patients were treated with T-cell lymphoblastic lymphoma-Berlin-Frankfurt-Münster group (BFM)-type treatment. LOH6q was observed in 12% of patients (25/217) and associated with unfavorable prognosis (pEFS 27% ± 9% vs 86% ± 3%; P < .0001). In 60% (70/116) of the patients, NOTCH1 mutations were detected and associated with favorable prognosis (pEFS 84% ± 5% vs 66% ± 7%; P = .021). Interestingly, NOTCH1 mutations were rarely observed in patients with LOH in 6q16. Both prognostic markers will be used as stratification criteria in coming Non-Hodgkin Lymphoma-BFM trials.


Assuntos
Cromossomos Humanos Par 6/genética , Perda de Heterozigosidade , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Mutação , Receptor Notch1/genética , Adolescente , Proteínas de Ciclo Celular/genética , Criança , Estudos de Coortes , Análise Mutacional de DNA , Proteínas F-Box/genética , Proteína 7 com Repetições F-Box-WD , Feminino , Variação Genética , Humanos , Incidência , Linfoma de Células T/epidemiologia , Masculino , Prognóstico , Ubiquitina-Proteína Ligases/genética
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