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1.
Blood Adv ; 3(14): 2118-2127, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31300419

RESUMO

FOXO1 has an oncogenic role in adult germinal center-derived lymphomas, in which mutations, predominately within the AKT recognition motif, cause nuclear retention of FOXO1, resulting in increased cell proliferation. To determine the prevalence and distribution of FOXO1 mutations in pediatric Burkitt lymphoma (BL), we sequenced a large number of sporadic and endemic BL patient samples. We report a high frequency of FOXO1 mutations in both sporadic and endemic BL at diagnosis, occurring in 23/78 (29%) and 48/89 (54%) samples, respectively, as well as 8/16 (50%) cases at relapse. Mutations of T24 were the most common in sporadic BL but were rare in endemic cases, in which mutations of residue S22, also within the AKT recognition motif, were the most frequent. FOXO1 mutations were almost always present in the major tumor cell clone but were not associated with outcome. Analysis of other recurrent mutations reported in BL revealed that FOXO1 mutations were associated with mutations of DDX3X and ARID1A, but not MYC, TCF3/ID3, or members of the phosphatidylinositol 3-kinase signaling pathway. We further show common nuclear retention of the FOXO1 protein, irrespective of mutation status, suggesting alternative unknown mechanisms for maintaining FOXO1 transcriptional activity in BL. CRISPR/Cas9 knockout of FOXO1 in an endemic cell line produced a significant decrease in cell proliferation, supporting an oncogenic role for FOXO1 in endemic BL. Thus, FOXO1 is frequently mutated in both sporadic and endemic BL and may offer a potential therapeutic target for pediatric BL patients worldwide.

3.
Lancet Child Adolesc Health ; 3(5): 322-331, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30885698

RESUMO

BACKGROUND: Wilms tumour is the most common childhood renal cancer and is genetically heterogeneous. While several Wilms tumour predisposition genes have been identified, there is strong evidence that further predisposition genes are likely to exist. Our study aim was to identify new predisposition genes for Wilms tumour. METHODS: In this exome sequencing study, we analysed lymphocyte DNA from 890 individuals with Wilms tumour, including 91 affected individuals from 49 familial Wilms tumour pedigrees. We used the protein-truncating variant prioritisation method to prioritise potential disease-associated genes for further assessment. We evaluated new predisposition genes in exome sequencing data that we generated in 334 individuals with 27 other childhood cancers and in exome data from The Cancer Genome Atlas obtained from 7632 individuals with 28 adult cancers. FINDINGS: We identified constitutional cancer-predisposing mutations in 33 individuals with childhood cancer. The three identified genes with the strongest signal in the protein-truncating variant prioritisation analyses were TRIM28, FBXW7, and NYNRIN. 21 of 33 individuals had a mutation in TRIM28; there was a strong parent-of-origin effect, with all ten inherited mutations being maternally transmitted (p=0·00098). We also found a strong association with the rare epithelial subtype of Wilms tumour, with 14 of 16 tumours being epithelial or epithelial predominant. There were no TRIM28 mutations in individuals with other childhood or adult cancers. We identified truncating FBXW7 mutations in four individuals with Wilms tumour and a de-novo non-synonymous FBXW7 mutation in a child with a rhabdoid tumour. Biallelic truncating mutations in NYNRIN were identified in three individuals with Wilms tumour, which is highly unlikely to have occurred by chance (p<0·0001). Finally, we identified two de-novo KDM3B mutations, supporting the role of KDM3B as a childhood cancer predisposition gene. INTERPRETATION: The four new Wilms tumour predisposition genes identified-TRIM28, FBXW7, NYNRIN, and KDM3B-are involved in diverse biological processes and, together with the other 17 known Wilms tumour predisposition genes, account for about 10% of Wilms tumour cases. The overlap between these 21 constitutionally mutated predisposition genes and 20 genes somatically mutated in Wilms tumour is limited, consisting of only four genes. We recommend that all individuals with Wilms tumour should be offered genetic testing and particularly, those with epithelial Wilms tumour should be offered TRIM28 genetic testing. Only a third of the familial Wilms tumour clusters we analysed were attributable to known genes, indicating that further Wilms tumour predisposition factors await discovery. FUNDING: Wellcome Trust.

4.
Eur J Cancer ; 110: 74-85, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30772656

RESUMO

Paediatric Strategy Forums have been created by the multistakeholder organisation, ACCELERATE, and the European Medicines Agency to facilitate dialogue between all relevant stakeholders and suggest strategies in critical areas of paediatric oncology drug development. As there are many medicines being developed for B-cell malignancies in adults but comparatively few in children with these malignancies, a Paediatric Strategy Forum was held to discuss the best approach to develop these products for children. It was concluded that as current frontline therapy is highly successful, despite associated acute toxicity, de-escalation of this or substitution of presently used drugs with new medicines can only be undertaken when there is an effective salvage regimen, which is currently not available. Therefore priority should be given to developing treatment for patients with relapsed and refractory mature B-cell lymphomas. The consensus of the clinicians attending the meeting was that CAR T-cells, T-cell engagers and antibody drug conjugates (excluding those with a vinca alkaloid-like drug) presently have the greatest probability of providing benefit in relapse in view of their mechanism of action. However, as producing autologous CAR T-cells currently takes at least 4 weeks, they are not products which could be quickly employed initially at relapse in rapidly progressing mature B-cell malignancies but only for the consolidation phase of the treatment. Global, industry-supported, academic-sponsored studies testing compounds from different pharmaceutical companies simultaneously should be considered in rare populations, and it was proposed that an international working group be formed to develop an overarching clinical trials strategy for these disease groups. Future Forums are planned for other relevant paediatric oncologic diseases with a high unmet medical need and relevant molecular targets.

5.
Cancer Cell ; 34(4): 626-642.e8, 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30300583

RESUMO

Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML.

6.
Pediatr Blood Cancer ; 65(4)2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29286565

RESUMO

Data on management of pediatric marginal zone lymphoma (MZL) are scarce. This retrospective study assessed characteristics and outcome in 66 patients who were <18 years old. Forty-four (67%) had an extranodal MZL (EMZL), 21 (32%) a nodal MZL (NMZL), and one patient a splenic MZL. Thirty-three patients (50%) received a variable combination of adjuvant chemotherapy/immunotherapy/radiotherapy, while the remainder, including 20 of 21 with NMZL, entered an active observation period. Overall survival was excellent (98 ± 2%), although 11 patients relapsed (17%; NMZL, n = 1; EMZL, n = 10), seven after any therapy and four after complete resection only. In conclusion, outcome of NZML, in particular, seems to be excellent after (in)complete resection and observation only.

7.
Front Immunol ; 9: 2912, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619276

RESUMO

Patients with inborn errors of immunity or DNA repair defects are at significant risk of developing malignancy and this complication of their underlying condition represents a substantial cause of morbidity and mortality. Whilst this risk is increasingly well-recognized, our understanding of the causative mechanisms remains incomplete. Diagnosing cancer is challenging in the presence of underlying co-morbidities and frequently other inflammatory and lymphoproliferative processes. We lack a structured approach to management despite recognizing the competing challenges of poor response to therapy and increased risk of toxicity. Finally, clinicians need guidance on how to screen for malignancy in many of these predisposing immunodeficiencies. In order to begin to address these challenges, we brought together representatives of European Immunology and Pediatric Haemato-Oncology to define the current state of our knowledge and identify priorities for clinical and research development. We propose key developmental priorities which our two communities will need to work together to address, collaborating with colleagues around the world.


Assuntos
Distúrbios no Reparo do DNA/complicações , Síndromes de Imunodeficiência/complicações , Neoplasias/diagnóstico , Neoplasias/terapia , Pesquisa , Alergia e Imunologia/tendências , Criança , Humanos , Comunicação Interdisciplinar , Oncologia/métodos , Oncologia/tendências , Neoplasias/complicações , Pediatria/métodos , Pediatria/tendências
8.
Blood ; 130(2): 167-175, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28512190

RESUMO

Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are rare histiocytic disorders induced by somatic mutation of MAPK pathway genes. BRAFV600E mutation is the most common mutation in both conditions and also occurs in the hematopoietic neoplasm hairy cell leukemia (HCL). It is not known if adult LCH or ECD arises from hematopoietic stem cells (HSCs), nor which potential blood borne precursors lead to the formation of histiocytic lesions. In this study, BRAFV600E allele-specific polymerase chain reaction was used to map the neoplastic clone in 20 adults with LCH, ECD, and HCL. BRAFV600E was tracked to classical monocytes, nonclassical monocytes, and CD1c+ myeloid dendritic cells (DCs) in the blood, and mutations were observed in HSCs and myeloid progenitors in the bone marrow of 4 patients. The pattern of involvement of peripheral blood myeloid cells was indistinguishable between LCH and ECD, although the histiocytic disorders were distinct to HCL. As reported in children, detection of BRAFV600E in peripheral blood of adults was a marker of active multisystem LCH. The healthy counterparts of myeloid cells affected by BRAF mutation had a range of differentiation potentials depending on exogenous signals. CD1c+ DCs acquired high langerin and CD1a with granulocyte-macrophage colony-stimulating factor and transforming growth factor ß alone, whereas CD14+ classical monocytes required additional notch ligation. Both classical and nonclassical monocytes, but not CD1c+ DCs, made foamy macrophages easily in vitro with macrophage colony-stimulating factor and human serum. These studies are consistent with a hematopoietic origin and >1 immediate cellular precursor in both LCH and ECD.


Assuntos
Células da Medula Óssea/patologia , Doença de Erdheim-Chester/diagnóstico , Células-Tronco Hematopoéticas/patologia , Histiocitose de Células de Langerhans/diagnóstico , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Alelos , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos CD1/genética , Antígenos CD1/imunologia , Células da Medula Óssea/imunologia , Diferenciação Celular , Células Dendríticas/imunologia , Células Dendríticas/patologia , Diagnóstico Diferencial , Doença de Erdheim-Chester/genética , Doença de Erdheim-Chester/imunologia , Doença de Erdheim-Chester/patologia , Feminino , Células Espumosas/imunologia , Células Espumosas/patologia , Expressão Gênica , Glicoproteínas/genética , Glicoproteínas/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Células-Tronco Hematopoéticas/imunologia , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/imunologia , Histiocitose de Células de Langerhans/patologia , Humanos , Imunofenotipagem , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/imunologia , Masculino , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/imunologia , Monócitos/imunologia , Monócitos/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/imunologia , Receptores Notch/genética , Receptores Notch/imunologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia
9.
Haematologica ; 102(7): 1247-1257, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28385782

RESUMO

Inhibition of monocarboxylate transporter 1 has been proposed as a therapeutic approach to perturb lactate shuttling in tumor cells that lack monocarboxylate transporter 4. We examined the monocarboxylate transporter 1 inhibitor AZD3965, currently in phase I clinical studies, as a potential therapy for diffuse large B-cell lymphoma and Burkitt lymphoma. Whilst extensive monocarboxylate transporter 1 protein was found in 120 diffuse large B-cell lymphoma and 10 Burkitt lymphoma patients' tumors, monocarboxylate transporter 4 protein expression was undetectable in 73% of the diffuse large B-cell lymphoma samples and undetectable or negligible in each Burkitt lymphoma sample. AZD3965 treatment led to a rapid accumulation of intracellular lactate in a panel of lymphoma cell lines with low monocarboxylate transporter 4 protein expression and potently inhibited their proliferation. Metabolic changes induced by AZD3965 in lymphoma cells were consistent with a feedback inhibition of glycolysis. A profound cytostatic response was also observed in vivo: daily oral AZD3965 treatment for 24 days inhibited CA46 Burkitt lymphoma growth by 99%. Continuous exposure of CA46 cells to AZD3965 for 7 weeks in vitro resulted in a greater dependency upon oxidative phosphorylation. Combining AZD3965 with an inhibitor of mitochondrial complex I (central to oxidative phosphorylation) induced significant lymphoma cell death in vitro and reduced CA46 disease burden in vivo These data support clinical examination of AZD3965 in Burkitt lymphoma and diffuse large B-cell lymphoma patients with low tumor monocarboxylate transporter 4 expression and highlight the potential of combination strategies to optimally target the metabolic phenotype of tumors.


Assuntos
Antineoplásicos/farmacologia , Linfoma de Burkitt/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Pirimidinonas/farmacologia , Simportadores/antagonistas & inibidores , Tiofenos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Metabolismo Energético/efeitos dos fármacos , Humanos , Ácido Láctico/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Pirimidinonas/uso terapêutico , Simportadores/genética , Simportadores/metabolismo , Tiofenos/uso terapêutico
10.
Haematologica ; 101(12): 1581-1591, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27515251

RESUMO

Children and adolescents with pre-existing conditions such as DNA repair defects or other primary immunodeficiencies have an increased risk of non-Hodgkin lymphoma. However, large-scale data on patients with non-Hodgkin lymphoma and their entire spectrum of pre-existing conditions are scarce. A retrospective multinational study was conducted by means of questionnaires sent out to the national study groups or centers, by the two largest consortia in childhood non-Hodgkin lymphoma, the European Intergroup for Childhood non-Hodgkin Lymphoma, and the international Berlin-Frankfurt-Münster Study Group. The study identified 213 patients with non-Hodgkin lymphoma and a pre-existing condition. Four subcategories were established: a) cancer predisposition syndromes (n=124, 58%); b) primary immunodeficiencies not further specified (n=27, 13%); c) genetic diseases with no increased cancer risk (n=40, 19%); and d) non-classifiable conditions (n=22, 10%). Seventy-nine of 124 (64%) cancer predispositions were reported in groups with more than 20 patients: ataxia telangiectasia (n=32), Nijmegen breakage syndrome (n=26), constitutional mismatch repair deficiency (n=21). For the 151 patients with a known cancer risk, 5-year event-free survival and overall survival rates were 40%±4% and 51%±4%, respectively. Five-year cumulative incidences of progression/relapse and treatment-related death as a first event were 22%±4% and 24%±4%, respectively. Ten-year incidence of second malignancy was 24%±5% and 7-year overall survival of the 21 patients with a second malignancy was 41%±11%. Patients with non-Hodgkin lymphoma and pre-existing conditions have an inferior survival rate with a large proportion of therapy-related deaths compared to patients with non-Hodgkin lymphoma and no pre-existing conditions. They may require special vigilance when receiving standard or modified/reduced-intensity chemotherapy or when undergoing allogeneic stem cell transplantation.


Assuntos
Comorbidade , Suscetibilidade a Doenças , Linfoma não Hodgkin/epidemiologia , Vigilância em Saúde Pública , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Progressão da Doença , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/terapia , Masculino , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Recidiva , Resultado do Tratamento
11.
Blood ; 127(16): 1998-2006, 2016 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-26869395

RESUMO

Prevention of central nervous system (CNS) relapse is critical for cure of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Despite this, mechanisms of CNS infiltration are poorly understood, and the timing, frequency, and properties of BCP-ALL blasts entering the CNS compartment are unknown. We investigated the CNS-engrafting potential of BCP-ALL cells xenotransplanted into immunodeficient NOD.Cg- ITALIC! Prkdc (ITALIC! scid) ITALIC! Il2rg (ITALIC! tm1Wjl)/SzJ mice. CNS engraftment was seen in 23 of 29 diagnostic samples (79%): 2 of 2 from patients with overt CNS disease and 21 of 27 from patients thought to be CNS negative by diagnostic lumbar puncture. Histologic findings mimic human pathology and demonstrate that leukemic cells transit the blood-cerebrospinal fluid barrier situated close to the dural sinuses, the site of recently discovered CNS lymphatics. Retrieval of blasts from the CNS showed no evidence for chemokine receptor-mediated selective trafficking. The high frequency of infiltration and lack of selective trafficking led us to postulate that CNS tropism is a generic property of leukemic cells. To test this, we performed serial dilution experiments which showed CNS engraftment in 5 of 6 mice after transplant of as few as 10 leukemic cells. Clonal tracking techniques confirmed the polyclonal nature of CNS-infiltrating cells, with multiple clones engrafting in both the CNS and periphery. Overall, these findings suggest that subclinical seeding of the CNS is likely to be present in most BCP-ALL patients at original diagnosis, and efforts to prevent CNS relapse should concentrate on effective eradication of disease from this site rather than targeting entry mechanisms.


Assuntos
Barreira Hematoencefálica/patologia , Movimento Celular/fisiologia , Sistema Nervoso Central/patologia , Infiltração Leucêmica/patologia , Leucócitos/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Animais , Células Cultivadas , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/secundário , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Transplante de Neoplasias , Recidiva , Transplante Heterólogo
12.
Children (Basel) ; 2(2): 146-73, 2015 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-27417356

RESUMO

Improving survival rates in children with malignancy have been achieved at the cost of a high frequency of late adverse effects of treatment, especially in intensively treated patients such as those undergoing haematopoietic stem cell transplantation (HSCT), many of whom suffer the high burden of chronic toxicity. Secondary malignant neoplasms (SMNs) are one of the most devastating late effects, cause much morbidity and are the most frequent cause of late (yet still premature) treatment-related mortality. They occur in up to 7% of HSCT recipients by 20 years post-HSCT, and with no evidence yet of a plateau in incidence with longer follow-up. This review describes the epidemiology, pathogenesis, clinical features and risk factors of the three main categories of post-HSCT SMNs. A wide range of solid SMNs has been described, usually occurring 10 years or more post-HSCT, related most often to previous or conditioning radiotherapy. Therapy-related acute myeloid leukaemia/myelodysplasia occurs earlier, typically three to seven years post-HSCT, mainly in recipients of autologous transplant and is related to previous alkylating agent or topoisomerase II inhibitor chemotherapy. Post-transplant lymphoproliferative disorders occur early (usually within two years) post-HSCT, usually presenting as Epstein-Barr virus-related B cell non-Hodgkin lymphoma.

13.
Pediatr Blood Cancer ; 62(6): 1055-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25382309

RESUMO

Hypereosinophilia is a rare phenomenon associated with childhood malignancy, predominantly acute lymphoblastic leukaemia. Causation is unclear and likely to have multiple mechanisms. We report a six year old boy presenting with hypereosinophilia and associated Loeffler endocarditis. Three months following his initial hypereosinophilia he developed cutaneous B-lymphoblastic lymphoma. Re-analysis of apparently uninvolved bone marrow, taken at initial presentation, revealed a single, previously unidentified, t(5;14)(q31;q32) positive cell. Using fluorescent in situ hybridisation, we demonstrate IL3/IgH@ fusion in cutaneous lymphoma cells. Our case confirms the association of hypereosinophilia and B-lymphoblastic lymphoma and strengthens the association between IL3 hypersecretion and hypereosinophilia.


Assuntos
Endocardite/etiologia , Síndrome Hipereosinofílica/etiologia , Cadeias Pesadas de Imunoglobulinas/genética , Interleucina-3/genética , Linfoma de Células B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Neoplasias Cutâneas/genética , Translocação Genética , Doença Aguda , Criança , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 5 , Humanos , Linfoma de Células B/complicações , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações
14.
EMBO Mol Med ; 5(1): 38-51, 2013 01.
Artigo em Inglês | MEDLINE | ID: mdl-23229821

RESUMO

Leukaemia-propagating cells are more frequent in high-risk acute B lymphoblastic leukaemia than in many malignancies that follow a hierarchical cancer stem cell model. It is unclear whether this characteristic can be more universally applied to patients from non-'high-risk' sub-groups and across a broad range of cellular immunophenotypes. Here, we demonstrate in a wide range of primary patient samples and patient samples previously passaged through mice that leukaemia-propagating cells are found in all populations defined by high or low expression of the lymphoid differentiation markers CD10, CD20 or CD34. The frequency of leukaemia-propagating cells and their engraftment kinetics do not differ between these populations. Transcriptomic analysis of CD34(high) and CD34(low) blasts establishes their difference and their similarity to comparable normal progenitors at different stages of B-cell development. However, consistent with the functional similarity of these populations, expression signatures characteristic of leukaemia propagating cells in acute myeloid leukaemia fail to distinguish between the different populations. Together, these findings suggest that there is no stem cell hierarchy in acute B lymphoblastic leukaemia.


Assuntos
Células-Tronco Neoplásicas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Animais , Antígenos CD34/metabolismo , Diferenciação Celular , Redes Reguladoras de Genes , Humanos , Imunofenotipagem , Camundongos , Modelos Biológicos , Transplante de Neoplasias , Células-Tronco Neoplásicas/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Transcriptoma , Transplante Heterólogo
15.
Blood ; 119(1): 196-205, 2012 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-22084312

RESUMO

Up to 15% of acute promyelocytic leukemia (APL) patients fail to achieve or maintain remission. We investigated a common G > A polymorphism at position -1377 (rs2234767) in the core promoter of the CD95 cell death receptor gene in 708 subjects with acute myeloid leukemia, including 231 patients with APL. Compared with the GG genotype, carrier status for the -1377A variant was associated with a significantly worse prognosis in APL patients. Carriers were more likely to fail remission induction (odds ratio = 4.22; 95% confidence interval, 1.41-12.6, P = .01), were more likely to die during the first 8 weeks of remission induction therapy (hazard ratio = 7.26; 95% confidence interval, 2.39-22.9, P = .0005), and had a significantly worse 5-year overall survival (odds ratio = 2.14; 95% confidence interval, 1.10-4.15, P = .03). The -1377A variant destroys a binding site for the SP1 transcriptional regulator and is associated with lower transcriptional activity of the CD95 promoter. Identifying patients at high risk of life-threatening events, such as remission induction failure, is a high priority in APL, especially because such events represent a major cause of death despite the introduction of differentiation therapy.


Assuntos
Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/mortalidade , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Receptor fas/genética , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Criança , Pré-Escolar , DNA de Neoplasias/genética , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Leucemia Promielocítica Aguda/tratamento farmacológico , Luciferases/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , RNA Interferente Pequeno/genética , Indução de Remissão , Fator de Transcrição Sp1/antagonistas & inibidores , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas , Adulto Jovem
16.
Genes Chromosomes Cancer ; 51(3): 250-6, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22072526

RESUMO

Casitas B-lineage lymphoma (CBL) proteins are RING finger ubiquitin E3 ligases that attenuate the signaling of receptor tyrosine kinases and are mutated in a number of myeloid disorders. In this study, mutational screening of the linker-RING domains of CBL and CBLB was performed by denaturing high performance liquid chromatography in a cohort of diagnostic (n = 180) or relapse (n = 46) samples from children with acute lymphoblastic leukemia. Somatic mutations were identified in three children, giving an overall incidence of 1.7% and involved small deletions affecting the intron/exon boundaries of exon 8, leading to skipping of exon 8 and abolishing E3 ligase function. Mutated primary samples were associated with constitutive activation of the RAS pathway and sensitivity to MEK inhibitors was shown. Thus, mutation of CBL is an alternative route to activate the RAS pathway and may identify children who are candidates for MEK inhibitor clinical trials.


Assuntos
Mutação , Proteína Oncogênica v-cbl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transdução de Sinais/genética , Adolescente , Sequência de Bases , Criança , Pré-Escolar , Cromatografia Líquida , Estudos de Coortes , Análise Mutacional de DNA , Éxons , Feminino , Humanos , Íntrons , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Masculino , Dados de Sequência Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Domínios RING Finger , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Recidiva , Reino Unido
17.
Pediatr Hematol Oncol ; 28(2): 106-14, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21214410

RESUMO

The percentage of chemotherapy-induced necrosis in primary tumors corresponds with outcome in several childhood malignancies, including high-risk metastatic diseases. In this retrospective pilot study, the authors assessed the importance of postchemotherapy necrosis in high-risk neuroblastoma with a histological and case notes review of surgically resected specimens. The authors reviewed all available histology of 31 high-risk neuroblastoma cases treated with COJEC (dose intensive etoposide and vincristine with either cyclophosphamide, cisplatin or carboplatin) or OPEC/OJEC (etoposide, vincristine and cyclophosphamide with alternating cisplatin [OPEC] or carboplatin [OJEC]) induction chemotherapy in 2 Children's Cancer & Leukaemia Group (CCLG) pediatric oncology centers. The percentage of postchemotherapy necrosis was assessed and compared with MYCN amplification status and overall survival. The median percentage of postchemotherapy tumor necrosis was 60%. MYCN status was available for 28 cases, of which 12 were amplified (43%). Survival in cases with ≥ 60% necrosis or ≥ 90% necrosis was not better than those with less necrosis, nor was percentage necrosis associated with survival using Cox regression. However, MYCN-amplified tumors showed a higher percentage of necrosis than non-MYCN-amplified tumors, 71.3% versus 37.2% (P = .006). This effect was not related to prechemotherapy necrosis and did not confer improved overall survival. Postchemotherapy tumor necrosis is higher in patients with MYCN amplification. In this study, postchemotherapy necrosis did not correlate with overall survival and should not lead to modification of postoperative treatment. However, these findings need to be confirmed in a larger prospective study of children with high-risk neuroblastoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Amplificação de Genes , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologia , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Carboplatina/administração & dosagem , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Lactente , Masculino , Proteína Proto-Oncogênica N-Myc , Necrose , Estadiamento de Neoplasias , Neuroblastoma/genética , Neuroblastoma/mortalidade , Projetos Piloto , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagem
18.
Cancer Cell ; 14(1): 47-58, 2008 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-18598943

RESUMO

We examined the leukemic stem cell potential of blasts at different stages of maturation in childhood acute lymphoblastic leukemia (ALL). Human leukemic bone marrow was transplanted intrafemorally into NOD/scid mice. Cells sorted using the B precursor differentiation markers CD19, CD20, and CD34 were isolated from patient samples and engrafted mice before serial transplantation into primary or subsequent (up to quaternary) recipients. Surprisingly, blasts representative of all of the different maturational stages were able to reconstitute and reestablish the complete leukemic phenotype in vivo. Sorted blast populations mirrored normal B precursor cells with transcription of a number of stage-appropriate genes. These observations inform a model for leukemia-propagating stem cells in childhood ALL.


Assuntos
Linfócitos B/imunologia , Imunofenotipagem , Células-Tronco Neoplásicas/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Adolescente , Animais , Antígenos CD19/análise , Antígenos CD20/análise , Antígenos CD34/análise , Transplante de Medula Óssea , Diferenciação Celular , Linhagem Celular Tumoral , Linhagem da Célula , Proliferação de Células , Separação Celular , Pré-Escolar , Citometria de Fluxo , Regulação Leucêmica da Expressão Gênica , Humanos , Imunoglobulinas/genética , Imunoglobulinas/metabolismo , Imunofenotipagem/métodos , Lactente , Recém-Nascido , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transplante Heterólogo
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