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1.
Medicine (Baltimore) ; 98(9): e14569, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30817574

RESUMO

BACKGROUND: The prognostic value of microRNA (miRNA) expression in T-cell acute lymphoblastic leukemia (T-ALL) has generated significant research interest in recent years. However, most diagnostic and prognostic studies with regards to miRNA expression have been focused on combined B cell and T cell lymphoblastic leukemia. There are very few studies reporting the prognostic effects of miRNA expression on T-ALL. Therefore, a pioneer systematic review and meta-analysis was proposed to explore the possibilities of miRNAs as viable prognostic markers in T-ALL. This study is intended to be useful as a guideline for future research into drug evaluation and targeting miRNA as a biomarker for the treatment and prognosis of T-ALL. METHODS: The systematic review will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. The study search will be conducted by using Cochrane, EMBASE, Medline, Science Direct, and SCOPUS bibliographic databases. The reference lists of included studies will be manually searched to further bolster the search results. A combination of keywords will be used to search the databases. DISCUSSION: To explore the effect of miRNA on prognosis, forest plots will be generated to assess pooled HR and 95% CI. Upregulation, downregulation, and deregulation of specific miRNAs will be individually noted and used to extrapolate patient prognosis when associated with risk factors involved in T-ALL. Subgroup analysis will be carried out to analyze the effect of deregulation of miRNA expression on patient prognosis. A fixed or random-effects model of meta-analysis will be used depending upon between-study heterogeneity. This systematic review and meta-analysis will identify and synthesize evidence to determine the prognosis of miRNA in T-ALL and suggest the possible miRNA from meta-analysis results to predict as a biomarker for further detection and treatment of T-ALL.


Assuntos
Metanálise como Assunto , MicroRNAs/sangue , Estudos Observacionais como Assunto , Leucemia-Linfoma Linfoblástico de Células T Precursoras/sangue , Revisão Sistemática como Assunto , Biomarcadores Tumorais/sangue , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Prognóstico , Projetos de Pesquisa , Fatores de Risco , Linfócitos T/metabolismo
3.
Ann Lab Med ; 39(2): 125-132, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30430774

RESUMO

BACKGROUND: Chromosomal abnormalities and common genetic rearrangements related to T-acute lymphoblastic leukemia (T-ALL) are not clear. We investigated T-cell receptor (TCR) rearrangement in Korean T-ALL patients by fragment analysis, examining frequency, association between clinicopathologic characteristics and TCR clonality, and feasibility for detecting minimal residual disease (MRD). METHODS: In 51 Korean patients diagnosed as having T-ALL, TCR rearrangement was analyzed using the IdentiClone TCR gene clonality assay (InVivoScribe Technologies, San Diego, CA, USA) from archived bone marrow specimens. Limit of detection (LOD) and clonal stability at relapse were evaluated. The association between clinical prognosis and TCR clonality was examind by age and immunophenotypic classification. RESULTS: Thirty-eight patients (74.5%) had 62 clonal products of TCRß, TCRγ, and/or TCRδ rearrangements at diagnosis. Children with T-ALL (<12 years) showed a higher frequency of clonality (93.8%) than adolescents/adults (65.7%; ≥12 years). Patients with a mature immunophenotype (84.4%) showed a relatively higher frequency of clonality than those with the immature immunophenotype (57.9%). Survival and event-free survival were not influenced by immunophenotype or TCR clonality. The LOD was 1%. Clonal evolution at the relapse period was noted. CONCLUSIONS: The overall detection rate of TCR clonality was 74.5%. Survival did not differ by TCR clonality or immunophenotype and age group. Fragment analysis of TCR rearrangement cannot be used to assess MRD due to low sensitivity. Further research on the relationship between prognosis and frequency of TCR rearrangements is needed, using more sensitive methods to detect clonality and monitor MRD.


Assuntos
Rearranjo Gênico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T gama-delta/genética , Adolescente , Adulto , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/metabolismo , Criança , Feminino , Humanos , Imunofenotipagem , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Intervalo Livre de Progressão , Recidiva , Indução de Remissão , Taxa de Sobrevida , Adulto Jovem
4.
Hematology ; 23(8): 470-477, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29486661

RESUMO

OBJECTIVE: Myeloid/lymphoid neoplasms with fibroblast growth factor receptor-1 (FGFR1) rearrangement are hematopoietic stem cell disorders with a poor prognosis, but no established standard therapy. METHODS: We experienced a patient with T-lymphoblastic lymphoma (LBL) associated with FGFR1 rearrangement who underwent cord blood transplantation, but died of pulmonary complication. We collected the clinical data of patients with FGFR1 rearrangement from the medical literature and analyzed 45 patients, including our patient. RESULTS: The primary diagnoses were myeloproliferative neoplasm (MPN) or myelodysplastic syndromes (MDS) in 14 and acute leukemia or LBL in 31. In MPN and MDS patients, the cumulative incidence of transformation to blast phase (BP) at 12 months was 46.2%. The 1-year overall survival (OS) from diagnosis in all cases was 43.1%. With regard to the impact of treatment response on survival, the achievement of complete response with a landmark at 2 months after diagnosis of BP was associated with a superior OS (40.0% vs. 26.0% P = 0.011 for 1-year OS from BP). Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in 13 patients, and the 1-year OS from allogeneic HSCT was 61.5%. The hazard ratio for mortality was 0.34 (95% CI, 0.08-1.51, P = 0.15) for allogeneic HSCT treated as a time-dependent covariate, which suggests that allogeneic HSCT may confer a clinical benefit. CONCLUSION: The further accumulation of clinical data is needed to determine the optimal therapeutic approach for these neoplasms.


Assuntos
Rearranjo Gênico , Neoplasias Hematológicas , Transtornos Mieloproliferativos , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adulto , Feminino , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/mortalidade , Transtornos Mieloproliferativos/terapia , Proteínas de Neoplasias/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo
5.
Sci Rep ; 8(1): 1088, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29348421

RESUMO

This study aimed to analyze the clinical characteristics and prognostic factors of patients, divided into over 40-year-old group or not, with precursor T-cell lymphoblastic lymphoma (Pre-T-LBL). Based on the retrospective analysis of the clinical data of 59 patients with Pre-T-LBL during the period from December 2010 to December 2015, albumin level, anemia, pleural or pericardial effusion, protocol, therapy response, mediastinal mass, lactate dehydrogenase (LDH), and international prognostic index (IPI) or age-adjusted international prognostic index (aaIPI) were summarized. For patients aged <40 years, factors correlating with poor progression-free survival (PFS) were pleural or pericardial effusion, regimen, albumin level and therapy response. Pleural or pericardial effusion, aaIPI score, regimen, LDH increased, albumin level, therapy response and mediastinal mass were all related with poor overall survival (OS). In the patients aged ≥40 years, only anemia associated with PFS. However, anemia, involvement of bone marrow and therapeutic response were all related with poor OS. In conclusion, the patients with Pre-T-LBL are characterized by a low incidence and bad prognosis. Different prognostic factors can be discovered for patients over 40-year-old with Pre-T-LBL comparing to the youngers. New prognostic evaluation factors should be explored for patients ≥40 years old.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Adolescente , Adulto , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Criança , Pré-Escolar , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Prognóstico , Modelos de Riscos Proporcionais , Resultado do Tratamento , Adulto Jovem
6.
J Pediatr Hematol Oncol ; 40(1): e1-e8, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29200162

RESUMO

NOTCH1/FBXW7 mutations trigger oncogenic NOTCH1 signaling and its downstream target genes play crucial roles in the molecular pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). In the present study, NOTCH1 and FBXW7 mutations were studied in 25 primary T-ALL samples. All 34 exons of NOTCH1 and hotspot exons (exon 9 and exon 10) of FBXW7 were polymerase chain reaction amplified and sequenced for mutations. Our results showed that 13/25 (52%) were NOTCH1-mutated, of which 11 patients (44%) showed mutation in the hotspot exons. Four patients (16%) had mutations in non-hotspot exons of NOTCH1. Notably, 2 T-ALL patients (8%) harbored mutations in both hotspot and non-hotspot exons of NOTCH1, whereas 2 patients (8%) had mutations in the hotspot exons of FBXW7. In all, 7 mutations were identified which were not previously reported. The real-time polymerase chain reaction study in 15 patients revealed that increased expression of activated NOTCH1 was found in NOTCH1/FBXW7 hotspot exon-mutated cases. In addition, NOTCH1/FBXW7-mutated patients had showed upregulated HES1, c-MYC, NOTCH3 gene expression. When survival analysis was performed including samples (n=50) from our previous study, an early treatment response and better survival was observed in NOTCH1/FBXW7 hotspot-mutated patients. Our study suggests that NOTCH1/FBXW7 hotspot-mutated T-ALL cases had better response to ALL BFM-95 protocol.


Assuntos
Proteína 7 com Repetições F-Box-WD/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Prognóstico , Receptor Notch1/genética , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Asparaginase , Criança , Pré-Escolar , Ciclofosfamida , Citarabina , Análise Mutacional de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Índia/epidemiologia , Lactente , Recém-Nascido , Masculino , Mercaptopurina , Metotrexato , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Prednisona , Análise de Sobrevida , Vincristina , Adulto Jovem
7.
J Pediatr Hematol Oncol ; 40(1): e34-e37, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28538509

RESUMO

We reviewed the immunophenotypic subtypes of pediatric T-cell lymphoblastic lymphoma in the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 study. Of the 104 patients, 40 patients each had sufficient data to evaluate the immunophenotypes and early T-cell precursor (ETP) subtype. Pro-T, pre-T, intermediate T, and mature T cells were observed in 1, 9, 21, and 9 cases, respectively. The 3-year event-free survival (EFS) rates of those with pro-T/pre-T, intermediate T, and mature T cells were 80.0±12.6%, 71.4±9.9%, and 88.9±10.5%, respectively (P=0.546). There were 8 and 32 cases of ETP and non-ETP subtypes, with 3-year EFS rates of 75.0±15.3% and 71.9±8.0%, respectively (P=0.828), indicating that the immunophenotypic subtype was not predictive of EFS in this study.


Assuntos
Células Precursoras de Linfócitos T/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/classificação , Prognóstico , Criança , Feminino , Humanos , Imunofenotipagem , Japão , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Estudos Retrospectivos , Análise de Sobrevida , Subpopulações de Linfócitos T/patologia
8.
Am J Hematol ; 93(1): 91-99, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29047158

RESUMO

Nelarabine, a water soluble prodrug of 9-ß-D-arabinofuranosylguanine (ara-G), is a T-cell specific purine nucleoside analogue. Given its activity in relapsed and refractory T acute lymphoblastic leukemia (T-ALL) and T lymphoblastic lymphoma (T-LBL), we sought to define its role in the frontline treatment of adult patients. Therefore, we conducted a single arm phase 2 study to determine the safety and efficacy of nelarabine in combination with hyper-CVAD in newly diagnosed patients. For induction/consolidation, patients received eight cycles of hyper-CVAD alternating with high-dose methotrexate and cytarabine plus two cycles of nelarabine given at a dose of 650 mg/m2 intravenously daily for 5 days. This was followed by thirty months of POMP maintenance chemotherapy with two additional cycles of nelarabine given instead of cycles 6 and 7 of POMP maintenance. Sixty-seven patients, including 40 with T-ALL and 26 with T-LBL, were enrolled. Complete response rates in both T-ALL and T-LBL were 87% and 100% respectively. Grade 3 to 4 neurotoxic adverse events were reported in 5 patients. There were 21 relapses (31%) including 2 after allogeneic stem cell transplantation. Median duration of follow-up was 42.5 months. The 3-year complete remission duration (CRD) and overall survival (OS) rates were 66% and 65%, respectively. Compared to our historic hyper-CVAD data, there was no survival benefit with the addition of nelarabine. In conclusion, hyper-CVAD plus nelarabine was well tolerated and active in the frontline treatment of adult T-ALL/LBL patients.


Assuntos
Arabinonucleosídeos/uso terapêutico , Imunofenotipagem/métodos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Adolescente , Adulto , Idoso , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Análise de Sobrevida , Adulto Jovem
9.
Ter Arkh ; 90(7): 38-50, 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30701921

RESUMO

AIM: The analysis of experience of nelarabine use in refractory/relapsed T-cell acute lymphoblastic leukemia (T-ALL) depending on the immunophenotype and the line of therapy. MATERIALS AND METHODS: All the patients with relapsed or refractory T-ALL aged from 0 to 18 years who received treatment with nelarabine as a part of the therapeutic element R6 were included in the study. For all patients a detailed immunological analysis of leukemia cells with discrimination of immunological variants TI, TII, TIII or TIV was performed. Patients administered with nelarabine as a first therapeutic element were referred to the first-line therapy group, other patients were referred to the second-line therapy group. Nelarabine was ad- ministered as intravenous infusion at a dose of 650 mg/m2, on days 1-5. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) was considered for all patients. RESULTS: From 2009 to 2017, 54 patients with refractory/relapsed T-ALL were treated with nelarabine. Five-year event-free survival (EFS) and overall survival (OS) was 28% for all patients, cumulative risk of relapse (CIR) was 27%. EFS was significantly higher in nelarabine first-line therapy group in comparison with second-line therapy group (34±8% vs 8±8%, p=0,05). In patients after allo-HSCT EFS, OS and CIR were 51±10%, 50±10% and 39,1±9,5% accordingly. The best results were achieved in patients with TI immunophenotype. No toxicity-related mortality as well as severe neurologic complications or discontinuation of therapy associated with use of nelarabine were reported. CONCLUSION: The use of nelarabine is an effective strategy for the treatment of relapsed and refractory T-ALL. The best treatment outcomes were obtained in patients with TI immunophenotype and in the first-line therapy group. Optimal dosage regimens can be established dur- ing controlled clinical trials.


Assuntos
Antineoplásicos/uso terapêutico , Arabinonucleosídeos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Arabinonucleosídeos/efeitos adversos , Arabinonucleosídeos/farmacocinética , Ensaios Clínicos como Assunto , Humanos , Injeções Intravenosas , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Intervalo Livre de Progressão , Recidiva
10.
Haematologica ; 102(12): 2086-2096, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28983060

RESUMO

In the European Intergroup EURO-LB02 trial, children and adolescents with lymphoblastic lymphoma underwent the non-Hodgkin lymphoma Berlin-Frankfurt-Münster protocol without prophylactic cranial radiotherapy. The primary aims of this trial were to test whether replacing prednisone with dexamethasone during induction increases event-free survival in the subgroups with T-cell lymphoblastic lymphoma and whether therapy duration could be reduced from 24 to 18 months (factorial design, randomizations). These questions could not be answered due to premature closure of the trial. Here we report on the secondary aims of the trial: whether the results of the NHL-BFM90 study could be reproduced and evaluation of disease features and prognostic factors. Three hundred and nineteen patients (66 with precursor B-cell lymphoblastic lymphoma, 233 with T-cell lymphoblastic lymphoma, 12 with mixed phenotype, 8 not classifiable) were enrolled. In induction, 215 patients received prednisone and 104 patients received dexamethasone. The median follow-up was 6.8 years (range, 3.0-10.3). The 5-year event-free survival was 82±2% [12 toxic deaths, 5 secondary malignancies, 43 non-response/relapse (central nervous system n=9; all received prednisone during induction)]. The event-free survival rate was 80±5% for patients with precursor B-cell lymphoblastic lymphoma, 82±3% for those with T-cell lymphoblastic lymphoma, and 100% for patients with a mixed phenotype. During induction, significantly more grade III/IV toxicities were observed in patients receiving dexamethasone, resulting in significant treatment delays. The number of toxic deaths did not differ significantly. The only variable associated with outcome was performance status at diagnosis. The 90% event-free survival rate for patients with T-cell lymphoblastic lymphoma shown in study NHL-BFM90 was not replicated, mainly due to more toxic deaths and central nervous system relapses. Dexamethasone in induction may prevent central nervous system relapse more effectively than prednisone but produces a higher burden of toxicity. (#NCT00275106).


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Dexametasona/toxicidade , Europa (Continente) , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Prednisona/toxicidade , Indução de Remissão/métodos , Análise de Sobrevida , Resultado do Tratamento
11.
Leuk Res ; 61: 33-38, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28869817

RESUMO

BACKGROUND: The Hypermethylation of Ras association domain family (RASSF) often plays a key role in malignant progression of solid tumors; however, their impact on the prognosis and survival of adult ALL patients remain elusive. METHODS: The frequency of the promoter methylation pattern of RASSF6 and RASSF10 were analyzed in the peripheral blood (PB) samples taken at the time of diagnosis of 45 ALL patients. The methylation-specific PCR (MSP) assay was used to detect the DNA methylation patterns. RESULTS: RASSF6 was frequently hypermethylated in patients diagnosed with pre-B-ALL (90.9%) and B-ALL (87.5%), followed by T-ALL (66.7%); whereas, RASSF10 methylation was more confined to T-ALL (80%) as compared to B-ALL (25%) and pre-B ALL (9.1%) patients. Moreover, hypermethylation of RASSF6 was significantly associated with a poor prognosis and shorter overall survival (OS) in patients with pre-B-ALL (log-rank test; P=0.041). CONCLUSION: RASSF6 and RASSF10 were frequently hypermethylated in the samples at the time of diagnosis of adult ALL patients. Our study represents the first report of methylation of RASSF6 at a high frequency in patients with pre-B ALL. Furthermore, hypermethylation of RASSF6 was significantly associated with inferior overall survival in pre-B ALL patients. It may suggest that the frequent epigenetic inactivation of RASSF6 plays an important role in the pathogenesis and progression of pre-B-ALL.


Assuntos
Metilação de DNA/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Prognóstico , Adulto Jovem
12.
Br J Haematol ; 179(2): 284-293, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28771663

RESUMO

Nelarabine is an antineoplastic agent approved for the treatment of relapsed/refractory T-lineage acute lymphoblastic leukaemia (T-ALL) or T-lineage acute lymphoblastic lymphoma (T-LBL). The purpose of this phase 4, multicentre, single-arm, observational, open-label trial was to provide additional data on the safety and efficacy of nelarabine under licensed conditions of use in children and young adults ≤21 years of age. Patients (N = 28) had a mean ± standard deviation age of 11·5 ± 4·6 years; 71% were male and 61% had a diagnosis of T-ALL. Adverse events (AEs) and treatment-related AEs were experienced by 46% and 21%, respectively, and included few haematological AEs and no haematological serious AEs. Neurological AEs from one of four predefined categories (peripheral and central nervous systems, mental status change and uncategorized) were reported in four patients. There were no AE-related treatment discontinuations/withdrawals. The overall response rate was 39.3%: complete response (CR), 35.7%; CR without full haematological recovery (CR*), 3.6%. Post-treatment stem cell transplantation was performed for 46% of the cohort. Median overall survival (OS) was 3·35 months for non-responders and not reached for responders (CR + CR*). The response rate, median OS, and safety profile of nelarabine in this disease setting and population were consistent with those reported previously.


Assuntos
Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Adolescente , Adulto , Criança , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Taxa de Sobrevida , Adulto Jovem
13.
Cell Physiol Biochem ; 42(4): 1458-1468, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28719899

RESUMO

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disease and is often accompanied by a variety of genetic abnormalities. Hence, our study aims to investigate the relationship between MMP-2 -1306C>T and MMP-9 -1562C>T polymorphisms and the risk and prognosis of T-ALL. METHODS: From April 2009 to February 2011, a total of 376 T-ALL patients were chosen as the case group. Meanwhile, 352 healthy people who passed routine health examinations were selected as the control group. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to detect the frequency of MMP-2 -1306C>T (rs243865) and MMP-9 -1562C>T (rs3918242) polymorphisms in the study subjects. The serum levels of MMP-2 and MMP-9 were detected using enzyme-linked immunosorbent assay (ELISA). A Kaplan-Meier analysis was employed to analyze the event-free survival (EFS) rates of the T-All patients with different MMP-2 and MMP-9 genotypes. A multivariate COX model was applied to analyze the relationship between MMP-2 and MMP-9 polymorphisms and the prognosis of T-ALL patients. A C-statistic and net reclassification index (NRI) was carried out to evaluate the predictive value of MMP-2 and MMP-9 gene polymorphisms using the Cox model. RESULTS: Compared to the control group, the genotypic frequency of MMP-2 -1306C>T (CT + TT) and MMP-9 -1562C>T (CT + TT) in the case group was significantly higher. The serum level of MMP-9 was markedly elevated in T-ALL patients with the CT + TT genotype compared to patients with the CC genotype. The results of the Kaplan-Meier analysis showed that the median EFS was lower in T-ALL patients with the CT + TT genotype of MMP-9 -1562C>T compared to patients with the CC genotype. The results of a multivariate analysis using the Cox proportional hazard model indicated that the MMP-9 -1562C>T polymorphism was associated with the prognosis of T-ALL patients. CONCLUSION: These results indicated that MMP-2 -1306C/T and MMP-9 -1562C/T polymorphisms might be associated with an increased risk of T-ALL. The MMP-9 -1562C>T polymorphism may also be related to the prognosis of T-ALL patients.


Assuntos
Predisposição Genética para Doença , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adulto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Feminino , Expressão Gênica , Frequência do Gene , Humanos , Masculino , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etnologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Prognóstico , Modelos de Riscos Proporcionais
14.
Zhongguo Dang Dai Er Ke Za Zhi ; 19(6): 620-626, 2017 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-28606226

RESUMO

OBJECTIVE: To study the expression of ß-integrin family members in children with T-cell acute lymphoblastic leukemia (T-ALL) and their significance. METHODS: Quantitative real-time PCR analyses were performed to assess the expression levels of ß-integrin family members in bone marrow samples from 22 children with newly-diagnosed T-ALL and 21 controls (16 children with non-malignant hematologic disease and 5 healthy donors with bone marrow transplantation). Jurkat cells were treated with integrin inhibitor arginine-glycine-aspartate (Arg-Gly-Asp, RGD) peptide. The cell viability and apoptosis rate were determined by CCK8 assay and flow cytometry respectively. RESULTS: The mRNA levels of integrins ß2, ß3, and ß5 were significantly lower in children with T-ALL than in controls (P<0.05). In T-ALL patients, high integrin ß3 expression was associated with lower white blood cell counts (<100×109/L), minimal residual disease (MRD) positivity, and day 33 bone marrow negative remission (P<0.05). In T-ALL patients, higher integrin ß5 expression was associated with relapse of T-ALL (P<0.05). Based on survival curve analysis, higher integrin ß3 expression was related to lower event-free survival and overall survival rates. RGD peptide treatment inhibited the proliferation of Jurkat cells and increased their apoptosis rate (P<0.05). CONCLUSIONS: ß-Integrin may play a role in the occurrence and development of T-ALL by affecting cell proliferation and apoptosis. The expression of integrin ß5 is closely related to the risk of relapse of T-ALL. The expression of integrin ß3 is closely related the treatment response and prognosis of T-ALL.


Assuntos
Cadeias beta de Integrinas/fisiologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Criança , Pré-Escolar , Feminino , Humanos , Cadeias beta de Integrinas/genética , Células Jurkat , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , RNA Mensageiro/análise
16.
Leukemia ; 31(12): 2594-2600, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28539671

RESUMO

The tumour suppressor gene PTEN is commonly altered in T-cell acute lymphoblastic leukaemia but its prognostic impact is still debated. We screened a cohort of 573 fully characterised adult and paediatric T-cell acute lymphoblastic leukaemia (T-ALL) patients for genomic PTEN abnormalities. PTEN-inactivating mutations and/or deletions were identified in 91 cases (16%), including 18% of paediatric (49/277) and 14% of adult cases (42/296). Thirty-four patients harboured only mutations, 12 cases demonstrated only large deletions and 9 only microdeletions. About 36 patients had combined alterations. Different mechanisms of PTEN inactivation predicted differences in the clinical outcome for both adult and paediatric patients treated according to the GRAALL03/05 and FRALLE2000 protocols. Whereas large deletions predicted lower 5-year overall survival (P=0.0053 in adults, P=0.001 in children) and disease-free survival (P=0.0009 in adults, P=0.0002 in children), mutations were not associated with a worse prognosis. The prognostic impact of PTEN loss is therefore linked to the underlying type of genomic abnormality, both in adult and paediatric T-ALLs, demonstrating that detailed analysis of the type of abnormality type would be useful to refine risk stratification.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , PTEN Fosfo-Hidrolase/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Adulto , Fatores Etários , Alelos , Biomarcadores Tumorais , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Éxons , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunofenotipagem , Lactente , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Prognóstico , Deleção de Sequência , Análise de Sobrevida , Fluxo de Trabalho , Adulto Jovem
17.
Leukemia ; 31(12): 2771-2779, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28546582

RESUMO

This study explores the regulation and importance of System L amino acid transport in a murine model of T-cell acute lymphoblastic leukemia (T-ALL) caused by deletion of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). There has been a strong focus on glucose transport in leukemias but the present data show that primary T-ALL cells have increased transport of multiple nutrients. Specifically, increased leucine transport in T-ALL fuels mammalian target of rapamycin complex 1 (mTORC1) activity which then sustains expression of hypoxia inducible factor-1α (HIF1α) and c-Myc; drivers of glucose metabolism in T cells. A key finding is that PTEN deletion and phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) accumulation is insufficient to initiate leucine uptake, mTORC1 activity, HIF1α or c-Myc expression in T cells and hence cannot drive T-ALL metabolic reprogramming. Instead, a key regulator for leucine transport in T-ALL is identified as NOTCH. Mass spectrometry based proteomics identifies SLC7A5 as the predominant amino acid transporter in primary PTEN-/- T-ALL cells. Importantly, expression of SLC7A5 is critical for the malignant transformation induced by PTEN deletion. These data reveal the importance of regulated amino acid transport for T-cell malignancies, highlighting how a single amino acid transporter can have a key role.


Assuntos
Aminoácidos/metabolismo , Redes e Vias Metabólicas , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Sistemas de Transporte de Aminoácidos/metabolismo , Animais , Transporte Biológico , Modelos Animais de Doenças , Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Knockout , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo
18.
Oncotarget ; 8(18): 30199-30216, 2017 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-28415816

RESUMO

New approaches are needed for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission with chemotherapy. Analysis of the effects of pan-PIM protein kinase inhibitors on human T-ALL cell lines demonstrated that the sensitive cell lines expressed higher PIM1 protein kinase levels, whereas T-ALL cell lines with NOTCH mutations tended to have lower levels of PIM1 kinase and were insensitive to these inhibitors. NOTCH-mutant cells selected for resistance to gamma secretase inhibitors developed elevated PIM1 kinase levels and increased sensitivity to PIM inhibitors. Gene profiling using a publically available T-ALL dataset demonstrated overexpression of PIM1 in the majority of early T-cell precursor (ETP)-ALLs and a small subset of non-ETP ALL. While the PIM inhibitors blocked growth, they also stimulated ERK and STAT5 phosphorylation, demonstrating that activation of additional signaling pathways occurs with PIM inhibitor treatment. To block these pathways, Ponatinib, a broadly active tyrosine kinase inhibitor (TKI) used to treat chronic myelogenous leukemia, was added to this PIM-inhibitor regimen. The combination of Ponatinib with a PIM inhibitor resulted in synergistic T-ALL growth inhibition and marked apoptotic cell death. Treatment of mice engrafted with human T-ALL with these two agents significantly decreased the tumor burden and improved the survival of treated mice. This dual therapy has the potential to be developed as a novel approach to treat T-ALL with high PIM expression.


Assuntos
Antineoplásicos/farmacologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Inibidores de Proteínas Quinases/uso terapêutico , Proteômica , Proteínas Proto-Oncogênicas c-pim-1/genética , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Leuk Lymphoma ; 58(6): 1433-1445, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27736268

RESUMO

Iron is an essential nutrient, acting as a catalyst for metabolic reactions that are fundamental to cell survival and proliferation. Iron complexed to transferrin is delivered to the metabolism after endocytosis via the CD71 surface receptor. We found that transformed cells from a murine PTEN-deficient T-cell lymphoma model and from T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LL) cell lines overexpress CD71. As a consequence, the cells developed an addiction toward iron whose chelation by deferoxamine (DFO) dramatically affected their survival to induce apoptosis. Interestingly, DFO displayed synergistic activity with three ALL-specific drugs: dexamethasone, doxorubicin, and L-asparaginase. DFO appeared to act through a reactive oxygen species-dependent DNA damage response and potentiated the action of an inhibitor of the PARP pathway of DNA repair. Our results demonstrate that targeting iron metabolism could be an interesting adjuvant therapy for acute lymphoblastic leukemia.


Assuntos
Quelantes de Ferro/farmacologia , Ferro/metabolismo , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , PTEN Fosfo-Hidrolase/deficiência , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Apoptose/efeitos dos fármacos , Asparaginase/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Quimioterapia Adjuvante , Dano ao DNA , Desferroxamina/farmacologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Expressão Gênica , Humanos , Quelantes de Ferro/uso terapêutico , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/mortalidade , Camundongos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Espécies Reativas de Oxigênio/metabolismo , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo
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