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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 311-315, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33812392

RESUMO

OBJECTIVE: To investigate the clinical features and prognostic factors of acute lymphoblastic leukemia (ALL) children with P2RY8-CRLF2 gene rearrangement. METHODS: A total of 108 children with B-cell ALL (B-ALL) were diagnosed and systematically treated according to Chinese Children's Leukemia Group (CCLG) -ALL 2008 in our hospital from January 2016 to December 2016. The 108 patients were divided into two groups according to the result of mutiplex polymerase chain reaction: group with P2RY8-CRLF2 gene rearrangement and group without P2RY8-CRLF2 gene rearrangement. The ALL children with P2RY8-CRLF2 gene rearrangement were all treated by CCLG-ALL 2008 high-risk group (HR) regimens, and the ALL children in group without P2RY8-CRLF2 gene rearrangement received different intensity chemotherapy according to clinical risk classification. RESULTS: Five (4 male and 1 female) out of 108 patients with B-ALL had P2RY8-CRLF2 gene rearrangement. In the 5 B-ALL patients with P2RY8-CRLF2 gene rearrangement, the median age of the was 4 (2-6) years old and the median WBC count was 26.2 (2.46-525.1)×109/L. These patients presented different immunophenotype, including 3 cases of common B-ALL and 2 cases of pre B-ALL. Four patients carried a normal karyotype and 1 patient carried 46, XY, der (20) [22]/46, XY[2]. For the children with P2RY8-CRLF2 gene rearrangement, 1 patient (20%) could not achieve complete remission (CR), and minimal residual disease (MRD) of 2 patients (40%) was higher than 1% on day 33 of induction chemotherapy; while in group without P2RY8-CRLF2 gene rearrangement, all the patient achieved CR, and MRD in 6 patients (5.8%) was higher than 1% on day 33 of induction chemotherapy. The 3 year event-free survival (EFS) of ALL children in group with P2RY8-CRLF2 gene rearrangement was significantly lower than that in group without P2RY8-CRLF2 gene rearrangement (60.0%±21.9% vs 85.9%±3.9%) (P<0.05). CONCLUSION: The early treatment response and prognosis of ALL children with P2RY8-CRLF2 gene rearrangement are worse, and more effective protocol is needed for this subtype patients.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Rearranjo Gênico , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Receptores de Citocinas/genética , Receptores Purinérgicos P2Y/genética
2.
Zhonghua Yi Xue Za Zhi ; 101(13): 926-933, 2021 Apr 06.
Artigo em Chinês | MEDLINE | ID: mdl-33789373

RESUMO

Objective: To classify and quantify IKZF1 mutant transcripts in B-cell acute lymphoblastic leukemia (B-ALL) by RNA sequencing (RNA-seq) and bioinformatics analysis. Methods: A cohort of 263 B-ALL cases was enrolled at Hebei Yanda Ludaopei Hospital from September 2018 to September 2020. An integrated bioinformatics pipeline was developed to adapt the classification and quantification of IKZF1 transcripts from RNA-seq and was applied to sequencing data of these cases. The IKZF1 mutant transcripts classified by RNA-seq analysis were compared with the qualitative reverse transcription PCR (RT-PCR). Results: IKZF1 mutant transcripts were identified in 53 B-ALL patients by RT-PCR and Sanger sequencing, among which IK6 and IK10 transcripts accounted for 67.9% (36/53) and 28.3% (15/53) respectively. Additionally, 2 patients were double positive for IK6 and IK10. RNA-seq analysis identified 51 patients with IKZF1 mutant transcripts. Compared with the RT-PCR result, the detection sensitivity and specificity of RNA-seq analysis reached 94.3% (50/53) and 99.5% (209/210), respectively. Among the 50 patients with IKZF1 mutant transcripts both in RNA-seq and RT-PCR analysis, the ratio of mutant transcripts to total IKZF1 transcripts in 6 patients was 0.14 (0.11, 0.35), which was significantly lower than that of the other 44 patients [0.88 (0.35, 0.97), Z=-3.945,P<0.001]. IKZF1 mutations mostly occurred in Ph+and Ph-like B-ALL, characterized by abnormal JAK-STAT pathway, and B-ALL with PAX5 translocation. Conclusions: Through the optimized bioinformatics analysis process, RNA-seq data can be used to classify and quantitatively analyze IKZF1 transcripts in B-ALL. Furthermore, the relative expression of mutant IKZF1 transcripts was found to cluster into two groups, and IKZF1 mutation was found often accompanied with PAX5 translocations.


Assuntos
Fator de Transcrição Ikaros , Leucemia-Linfoma Linfoblástico de Células Precursoras , Linfócitos B/metabolismo , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Isoformas de Proteínas , Transcriptoma
4.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498175

RESUMO

Whilst the survival rates of childhood acute lymphoblastic leukemia (ALL) have increased remarkably over the last decades, the therapy resistance and toxicity are still the major causes of treatment failure. It was shown that overexpression of heme oxygenase-1 (HO-1) promotes proliferation and chemoresistance of cancer cells. In humans, the HO-1 gene (HMOX1) expression is modulated by two polymorphisms in the promoter region: (GT)n-length polymorphism and single-nucleotide polymorphism (SNP) A(-413)T, with short GT repeat sequences and 413-A variants linked to an increased HO-1 inducibility. We found that the short alleles are significantly more frequent in ALL patients in comparison to the control group, and that their presence may be associated with a higher risk of treatment failure, reflecting the role of HO-1 in chemoresistance. We also observed that the presence of short alleles may predispose to develop chemotherapy-induced neutropenia. In case of SNP, the 413-T variant co-segregated with short or long alleles, while 413-A almost selectively co-segregated with long alleles, hence it is not possible to determine if SNPs are actually of phenotypic significance. Our results suggest that HO-1 can be a potential target to overcome the treatment failure in ALL patients.


Assuntos
Neutropenia Febril Induzida por Quimioterapia/genética , Resistencia a Medicamentos Antineoplásicos/genética , Heme Oxigenase-1/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Células Cultivadas , Neutropenia Febril Induzida por Quimioterapia/etiologia , Criança , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Regiões Promotoras Genéticas
5.
Zhonghua Bing Li Xue Za Zhi ; 50(1): 49-54, 2021 Jan 08.
Artigo em Chinês | MEDLINE | ID: mdl-33396987

RESUMO

Objective: To study the diagnostic clues and significance in serous effusion cytology associated with lymphoblatic lymphoma/acute lymphoblastic leukemia (LBL/ALL). Methods: Forty-five serous effusion specimens with final diagnosis of LBL/ALL were collected from August 2011 to December 2019 at the First Affiliated Hospital of Zhengzhou University. All cases were reviewed for their clinical profiles, cytomorphologic features and ancillary studies. Cell blocks and immunocytochemistry were prepared in 22 cases; flow cytometric immunophenotyping was performed in three cases and gene rearrangement analysis (T-cell recepter, TCR and immunoglobulin, Ig) was performed in five cases. Results: Among the 45 cases, there were 35 males and 10 females with male to female ratio of 3.5∶1.0. The median age was 15 years. Mediastinal mass was the initial presentation in 39 patients (86.7%) and high LDL level were observed in 34 patients (75.6%). Microscopically, the majority of the specimens (86.7%) were hypercellular. The smears demonstrated dispersed lymphoblasts that were predominantly small to intermediate in size with scanty basophilic cytoplasm and irregular or convoluted nuclei with fine chromatin condensation and inconspicuous nucleoli. Mitoses were frequently observed. Karyorrhexis and apoptosis were seen in all cases. By immunophenotyping, TdT was expressed in 19 cases (86.4%) and CD99 in 20 cases (90.9%). Ki-67 expression varied from 65% to 95%. Flow cytometry in three cases demonstrated positivity for TdT, CD2, CD3 and CD7. Monoclonal TCR gene rearrangement was found in 4 of 5 cases, and both monoclonal TCR and Igκ gene were found in 1 case. Conclusions: In LBL/ALL, primary diagnosis could be made basing on clinical features (younger male patients with a mediastinum mass) and cytomorphology (monotonous, small to medium sized lymphoid cells with prominent irregular nuclei, fine chromatin and frequent mitoses, karyorrhexis and apoptosis). If immunocytochemistry and other ancillary studies are performed, the accuracy and reliability of the results could be improved.


Assuntos
Linfoma não Hodgkin , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Citodiagnóstico , Feminino , Humanos , Imunofenotipagem , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Reprodutibilidade dos Testes
6.
Environ Health Prev Med ; 26(1): 2, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397280

RESUMO

OBJECTIVES: We performed an updated meta-analysis to clarify the relationship between the CEBPE rs2239633 polymorphism and the childhood acute lymphoblastic leukemia (CALL) susceptibility. METHODS: All the case-control studies were updated on October 5, 2020, through Web of Science, PubMed, Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI) electronic database. The heterogeneity in the study was tested by the Q test and I2, and then the random ratio or fixed effect was utilized to merge the odds ratios (OR) and 95% confidence interval (CI). We also performed sensitivity analysis to estimate the impact of individual studies on aggregate estimates. Publication bias was investigated by using funnel plot and Egger's regression test. All statistical analyses were performed using Stata 12.0. RESULTS: A total of 20 case-control studies were selected, including 7014 patients and 16,428 controls. There was no association of CEBPE rs2239633 polymorphism with CALL (CC vs CT + TT: OR = 1.08, 95% CI = 0.94-1.26; CC + CT vs TT: OR = 1.10, 95% CI = 0.94-1.30; C vs T: OR = 1.02, 95% CI = 0.92-1.13). In the subgroup analysis by ethnicity, there is no significant association of this polymorphism and CALL risks among Asian and Caucasian populations in the three genetic models (CC vs CT + TT, CC + CT vs TT, and C vs T). CONCLUSION: This meta-analysis found no significant association between the CEBPE rs2239633 polymorphism and susceptibility to CALL.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Criança , Pré-Escolar , Humanos , Lactente
7.
Cancer Sci ; 112(3): 1235-1250, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33393145

RESUMO

Acute lymphoblastic leukemia (ALL) is an aggressive hematological cancer that mainly affects children. Relapse and chemoresistance result in treatment failure, underlining the need for improved therapies. BTB and CNC homology 2 (BACH2) is a lymphoid-specific transcription repressor recognized as a tumor suppressor in lymphomas, but little is known about its function and regulatory network in pediatric ALL (p-ALL). Herein, we found aberrant BACH2 expression at new diagnosis not only facilitated risk stratification of p-ALL but also served as a sensitive predictor of early treatment response and clinical outcome. Silencing BACH2 in ALL cells increased cell proliferation and accelerated cell cycle progression. BACH2 blockade also promoted cell adhesion to bone marrow stromal cells and conferred cytarabine (Ara-C)-resistant properties to leukemia cells by altering stromal microenvironment. Strikingly, we identified FOS, a transcriptional activator competing with BACH2, as a novel downstream target repressed by BACH2. Blocking FOS by chemical compounds enhanced the effect of Ara-C treatment in both primary p-ALL cells and pre-B-ALL-driven leukemia xenografts and prolonged the survival of tumor-bearing mice. These data highlight an interconnected network of BACH2-FOS, disruption of which could render current chemotherapies more effective and offer a promising therapeutic strategy to overcome Ara-C resistance in p-ALL.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Fatores de Transcrição de Zíper de Leucina Básica/genética , Proliferação de Células/genética , Criança , Pré-Escolar , Citarabina/farmacologia , Citarabina/uso terapêutico , Feminino , Regulação Leucêmica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Lactente , Masculino , Células-Tronco Mesenquimais , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Cultura Primária de Células , Células Tumorais Cultivadas , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Nat Rev Cancer ; 21(2): 122-137, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33328584

RESUMO

Although much work has focused on the elucidation of somatic alterations that drive the development of acute leukaemias and other haematopoietic diseases, it has become increasingly recognized that germline mutations are common in many of these neoplasms. In this Review, we highlight the different genetic pathways impacted by germline mutations that can ultimately lead to the development of familial and sporadic haematological malignancies, including acute lymphoblastic leukaemia, acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Many of the genes disrupted by somatic mutations in these diseases (for example, TP53, RUNX1, IKZF1 and ETV6) are the same as those that harbour germline mutations in children and adolescents who develop these malignancies. Moreover, the presumption that familial leukaemias only present in childhood is no longer true, in large part due to the numerous studies demonstrating germline DDX41 mutations in adults with MDS and AML. Lastly, we highlight how different cooperating events can influence the ultimate phenotype in these different familial leukaemia syndromes.


Assuntos
Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Progressão da Doença , Humanos , Fenótipo
10.
Methods Mol Biol ; 2185: 77-94, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33165844

RESUMO

Although new techniques (i.e., droplet digital-PCR, next-generation sequencing, advanced flow cytometry) are being developed, DNA-based allele-specific real-time quantitative (RQ)-PCR is still the gold standard for sensitive and accurate immunoglobulin/T cell receptor (IG/TR)-based minimal residual disease (MRD) monitoring, allowing the detection of up to 1 leukemic cell in 100,000 normal lymphoid cells. We herewith describe the standard PCR procedure which has been developed and standardized (with minor modification in single labs) through the last 20 years of activity of the EuroMRD Consortium, a volunteer activity of expert laboratories that is continuously providing education, standardization, quality control rounds, and guidelines for interpretation of RQ-PCR data.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos B , Receptores de Antígenos de Linfócitos T , Humanos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo
11.
Zhonghua Xue Ye Xue Za Zhi ; 41(11): 896-902, 2020 Nov 14.
Artigo em Chinês | MEDLINE | ID: mdl-33333691

RESUMO

Objective: To evaluate the predictive role of ETV6-RUNX1 fusion gene in protocol CCLG-ALL-2008 as well as identify the prognostic factors that influence the outcome of ALL with ETV6-RUNX1 fusion gene. Methods: One hundred and seventy-eight patients newly diagnosed with pediatric acute lymphoblastic leukemia with ETV6-RUNX1 rearrangement from April 2008 to April 2015 were enrolled in CCLG-ALL-2008. The follow up period ended in July 2018; we performed retrospective analyses of their data to determine the efficacy of the regimen and the prognostic factors. Results: The median age of the study population (178 pediatric patients) , including 100 boys and 78 girls was 4 (1-13) y, and the median white blood cell count at diagnosis was 9.46 (1.25-239.83) ×10(9)/L. Three patients died, and 1 was lost to follow up by the end of the first induction chemotherapy, resulting in an induced remission rate of 97.8% (174/178) . The cumulative incidence of relapse was 15.9% with a median follow up of 73.5 mon. Total 83.3% of the relapse cases were those of isolated bone marrow relapse, while 79.2% of the cases were those of late relapse. The median interval time between relapse and first complete remission was 35.5 mon (range, 1-62 months) . One of the 5 patients with early recurrence and 7 of the 19 with late recurrence cases survived. The 5-year-OS and 5-year-EFS of ETV6-RUNX1 positive children was (89.4±2.4) % and (82.1±6.9) %, respectively. The estimated 10-year-OS and 10-year-EFS of ETV6-RUNX1 positive children was (88.6±2.5) % and (77.3±4.0) %, respectively. The Kaplan-Meier method and Log-rank test were used to estimate and compare the survival. Univariate statistical analysis showed that poor prognostic factors that influenced survival included central nervous system state 2 at diagnosis, poor prednisone response, high risk, gene positivity after induction chemotherapy, as well as MRD positivity and gene positivity at the 12(th) week. In the multivariate analysis, only the central nervous system state 2 at diagnosis and MRD positivity at the 12(th) week were associated with the outcome. Conclusion: ETV6-RUNX1-positive ALL is a subgroup with a favorable prognosis as per the CCLG-ALL-2008 protocol. Patients with ETV6-RUNX1 should be given more intensive therapy, including hematopoietic stem cell transplantation when they are CNS2 at diagnosis or have high level of MRD at the 12(th) week after treatment.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Subunidade alfa 2 de Fator de Ligação ao Core , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Estudos Retrospectivos
12.
Zhonghua Xue Ye Xue Za Zhi ; 41(11): 908-914, 2020 Nov 14.
Artigo em Chinês | MEDLINE | ID: mdl-33333693

RESUMO

Objective: To evaluate the association of TP53 mutations with the clinical outcomes of Ph-negative B-ALL following allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: Total 300 patients with Ph-negative B-ALL who underwent allo-HSCT at the Hebei Yanda Ludaopei Hospital from May 2012 to May 2017 were retrospectively analyzed; their clinical characteristics, TP53 gene mutation type, and association between TP53 mutations and transplantation outcomes, including leukemia-free survival (LFS) , overall survival (OS) , non-relapse mortality (NRM) , relapse, and GVHD, were evaluated. Results: Total 23 patients had TP53 mutations; all the TP53 mutations affected P53'DNA-binding domain. The 5-year-LFS, OS, and RI were 34.8% and 62.3% (P=0.001) , 41.9% and 65.1% (P=0.020) , and 47.8% and 14.8% (P=0.000) , respectively, for TP53 mutations and wild-type TP53 patients. However, there were no significant differences in NRM and GVHD. Multivariate analysis showed that TP53 mutations remained adverse prognostic factors for LFS, OS, and RI after allo-HSCT. Conclusion: Some patients with TP53 mutations can achieve long-term survival with allo-HSCT. TP53 mutations are adverse prognostic factors for Ph-negative B-ALL patients who undergo allo-HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteína Supressora de Tumor p53/genética , Doença Aguda , Humanos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento
13.
PLoS One ; 15(12): e0243657, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33338050

RESUMO

BCR-ABL1 fusion gene is the driver mutation of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Although the prognostic value of BCR-ABL1 isoforms in Ph+ ALL patients has been investigated in numerous studies in the tyrosine kinase inhibitor (TKI) era, the results were still conflicting. Hence we performed herein the meta-analysis to comprehensively assess the impact of BCR-ABL1 isoforms on the clinical outcomes of Ph+ ALL patients. Systematic literature review was conducted in PubMed, Embase, and Cochrane databases with the data access date up to June 15, 2020. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Furthermore, subgroup analyses were performed to assess the robustness of the associations. Nine studies with a total number of 1582 patients were eligible for this meta-analysis. Combined HRs suggested that p210 was slightly associated with inferior event-free survival (EFS) (HR = 1.34, 95% CI 1.05-1.72). The overall survival (OS) was not significantly affected (HR = 1.15, 95% CI 0.92-1.45). In subgroup analyses, the HRs showed a trend toward adverse impact of p210 on clinical outcomes. However, the confidence intervals were not crossing the null value only in a minority of subgroups including Caucasian studies, first-generation TKI treated cohort and transplant cohort. Our findings suggested that p210 might pose a mild adverse impact on the EFS of Ph+ ALL patients. This effect might be compromised by the use of second- or third-generation TKIs. Further studies are needed to verify our conclusions.


Assuntos
Proteínas de Fusão bcr-abl/genética , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Intervalo Livre de Doença , Humanos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Isoformas de Proteínas/genética
14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1523-1527, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067948

RESUMO

OBJECTIVE: To investigate the expression of Hsa-miR-9 in children with acute lymphoblastic leukemia (ALL) and its relationship with CDX2 gene. METHODS: The clinical data of 130 patients with ALL were collected from nearly five years in our hospital, and in the same period 60 healthy children in the same age were selected as control group. Real-time fluorescent quantitative PCR (qRT-PCR) was applied to examine the expression of Hsa-miR-9 and CDX2 gene of the two groups, the relationship between Hsa-miR-9 expression and ALL patients' clinical characteristics, survival time, CDX2 expression were analyzed. RESULTS: The expression level of Hsa-miR-9 in ALL children was significantly lower than that in the healthy control group (P<0.001). The expression of Hsa-miR-9 in ALL children related with serum WBC, infiltrating lymph nodes, splenomegaly, and risk grade (P<0.05). The median survival time of ALL children with high expression of Hsa-miR-9 was significantly longer than that of the ALL children with low expression (P<0.001). Hsa-miR-9 expression significantly correlated with CDX2 gene expression in ALL children at different treatment stages (P<0.05). CONCLUSION: The expression of Hsa-miR-9 decreases in children with ALL, and ALL children with high expression of Hsa-miR-9 have a longer overall survival time. The expression of hsa-miR-9 in ALL children closely related with CDX2 gene.


Assuntos
MicroRNAs , Leucemia-Linfoma Linfoblástico de Células Precursoras , Fator de Transcrição CDX2/genética , Criança , Humanos , MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Reação em Cadeia da Polimerase em Tempo Real
15.
N Engl J Med ; 383(17): 1613-1623, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33085860

RESUMO

BACKGROUND: Outcomes in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission is a primary goal of treatment. METHODS: We conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL (with no upper age limit). Dasatinib plus glucocorticoids were administered, followed by two cycles of blinatumomab. The primary end point was a sustained molecular response in the bone marrow after this treatment. RESULTS: Of the 63 patients (median age, 54 years; range, 24 to 82) who were enrolled, a complete remission was observed in 98%. At the end of dasatinib induction therapy (day 85), 29% of the patients had a molecular response, and this percentage increased to 60% after two cycles of blinatumomab; the percentage of patients with a molecular response increased further after additional blinatumomab cycles. At a median follow-up of 18 months, overall survival was 95% and disease-free survival was 88%; disease-free survival was lower among patients who had an IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both [i.e., IKZF1 plus]). ABL1 mutations were detected in 6 patients who had increased minimal residual disease during induction therapy, and all these mutations were cleared by blinatumomab. Six relapses occurred. Overall, 21 adverse events of grade 3 or higher were recorded. A total of 24 patients received a stem-cell allograft, and 1 death was related to transplantation (4%). CONCLUSIONS: A chemotherapy-free induction and consolidation first-line treatment with dasatinib and blinatumomab that was based on a targeted and immunotherapeutic strategy was associated with high incidences of molecular response and survival and few toxic effects of grade 3 or higher in adults with Ph-positive ALL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA LAL2116 D-ALBA EudraCT number, 2016-001083-11; ClinicalTrials.gov number, NCT02744768.).


Assuntos
Anticorpos Biespecíficos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dasatinibe/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia de Consolidação , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Mutação , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Indução de Remissão , Análise de Sobrevida , Resultado do Tratamento
16.
Ann Hematol ; 99(11): 2611-2617, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980888

RESUMO

EP300-ZNF384 fusion is a rare recurrent cytogenetic abnormality associated with B cell acute lymphoblastic leukemia (B-ALL), which was rarely studied in Chinese patient cohort. Here, we used a customized RNA fusion gene panel to investigate gene fusions in 56 selected acute leukemia patients without conventional genetic abnormalities. Two EP300-ZNF384 fusion forms were detected in ten cases, which were in-frame fusions of EP300 exon 6 fused with exon 3 or 2 of ZNF384. The fusions led to the lack of most functional domains of EP300. We firstly reported EP300-ZNF384 fusion in a mixed-phenotype acute leukemia (MPAL) patient whose CD33 and CD13 were negative. The rest nine B-ALL patients with EP300-ZNF384 fusion expressed CD33 and/or CD13. Fifty-six percent of B-ALL patients (5/9) with EP300-ZNF384 fusion were positive with CD10. After the diagnosis of EP300-ZNF384 fusion, 70% of the patients achieved remission after chemotherapy. Our observations indicated that EP300-ZNF384 fusion consists of a distinct subgroup of B-ALL with a characteristic immunophenotype. These patients are sensitive to current chemotherapy regimen and have an excellent outcome.


Assuntos
Proteína p300 Associada a E1A , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras , RNA Neoplásico , Análise de Sequência de RNA , Transativadores , Adulto , Estudos de Coortes , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismo , Feminino , Humanos , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Transativadores/genética , Transativadores/metabolismo
17.
Lancet Haematol ; 7(10): e715-e723, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32976751

RESUMO

BACKGROUND: The interferon lambda 4 gene (IFNL4) regulates immune responses by controlling the production of IFNλ4, a type III interferon. We hypothesised that IFNλ4 could play a role in infection clearance or alloreactivity in patients with acute leukaemia who received a myeloablative 10/10 HLA-matched haematopoietic stem-cell transplantation (HSCT). Therefore, we aimed to assess the association between recipient and donor IFNL4 genotype with post-HSCT survival outcomes in patients with acute leukaemia. METHODS: We did a two-stage retrospective cohort study using the Center for International Blood and Marrow Transplant Research (CIBMTR) repository and database, in which nearly all patients underwent the procedure in the USA. We included patients with acute myeloid leukaemia or acute lymphocytic leukaemia, who received a HSCT at any age from an unrelated 10/10 HLA-matched donor, with a myeloablative conditioning regimen, between Jan 1, 2000, and Dec 31, 2008, and had a pre-HSCT recipient or donor blood sample available. The discovery dataset included patients from an existing National Cancer Institute (NCI) cohort of the CIBMTR database, in which donor and recipient IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) were genotyped with TaqMan assays. According to their genotype, donors and recipients were categorised into IFNL4-positive, if they had at least one copy of the allele that supports the production of IFNλ4, or IFNL4-null for the analyses. The findings were independently validated with patients from the DISCOVeRY-BMT cohort (validation dataset) with existing Illumina array genotype data. We also did a combined analysis using data from patients included in both the NCI and DISCOVeRY-BMT cohorts. FINDINGS: We assessed 404 patients (who had a HSCT from Jan 9, 2004, to Dec 26, 2008) in the discovery dataset and 1245 patients in the validation dataset (HSCT Jan 7, 2000, to Dec 26, 2008). The combined analysis included 1593 overlapping participants in both cohorts. Donor, but not recipient IFNL4-positive genotype was associated with increased risk of non-relapse mortality (HR 1·60, 95% CI 1·23-2·10; p=0·0005 in the discovery dataset; 1·22, 1·05-1·40; p=0·0072 in the validation dataset; and 1·27, 1·12-1·45; p=0·0001 in the combined dataset). Associations with post-HSCT overall survival were as follows: HR 1·24, 95% CI 1·02-1·51; p=0·034 in the discovery dataset; 1·10, 0·98-1·20; p=0·10 in the validation dataset; and 1·11, 1·02-1·22; p=0·018 in the combined dataset. INTERPRETATION: Prioritising HSCT donors with the IFNL4-null genotype might decrease non-relapse mortality and improve overall survival without substantially limiting the donor pool. If these findings are validated, IFNL4 genotype could be added to the donor selection algorithm. FUNDING: The National Cancer Institute Intramural Research Program. For full funding list see Acknowledgments.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Interleucinas/genética , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Feminino , Genótipo , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos Retrospectivos , Resultado do Tratamento , Doadores não Relacionados , Adulto Jovem
18.
Anticancer Res ; 40(10): 5751-5756, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988902

RESUMO

BACKGROUND/AIM: A single study has shown positive association and genotype-phenotype correlation between metalloproteinase-9 (MMP-9) promoter genotypes and adult acute lymphocytic leukemia (ALL). However, there is no report about childhood ALL. Thus, this study aimed at examining the role of MMP-9 rs3918242 genotypes in childhood ALL risk. PATIENTS AND METHODS: A total of 266 childhood ALL cases and 266 healthy controls in Taiwan were examined for their MMP-9 rs3918242 genotypes via polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The MMP-9 rs3918242 CT or TT genotype carriers only had a slightly increased risk compared with CC carriers (p=0.6386 and 0.6005, respectively). The allelic frequency analysis also supported the idea that the variant T allele at MMP-9 rs3918242 is not differentially distributed between the case and control groups (p=0.4834). CONCLUSION: MMP-9 rs3918242 genotypes may indirectly influence the risk of childhood ALL. Further validations in other populations and analysis of the detail mechanisms are needed.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Metaloproteinase 9 da Matriz/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto , Alelos , Criança , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Regiões Promotoras Genéticas/genética
19.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(10): 1092-1096, 2020 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-32924108

RESUMO

OBJECTIVE: To analyze the laboratory and clinical features and prognosis of patients with acute lymphoblastic leukemia (ALL) and 11q23/MLL gene rearrangement. METHODS: A total of 725 patients with ALL were enrolled. The 11q23/MLL gene rearrangement and its partner genes were detected. The clinical and laboratory features and prognosis of patients with MLL gene rearrangement were analyzed. RESULTS: MLL gene rearrangement was detected in 42 cases (5.8%) of the patients, with the dominant immunophenotype being pro-B-ALL. Among the partner genes, the MLL/AF4 was the most common. Compared with the non-MLL/AF4 group, the MLL/AF4 group had higher white blood cell and immature cell counts. No significant difference was found in complete remission and 1-year overall survival (OS) rates between the two groups (P> 0.05). Compared with the non-MLL/AF4 group, the MLL/AF4 group had a higher recurrence rate (P<0.05) and a lower 3-year OS rate (P<0.05). Compared with the untransplantation group, the transplantation group had higher 2-year OS and progress free survival rates (P<0.05). Multivariate analysis suggested age ≤1 year, MLL/AF4 positive, early recurrence, and allogeneic hematopoietic stem cell transplant (Allo-HSCT) to be independent factors which can influence the survival of ALL patients with 11q23/MLL rearrangement (P<0.05). CONCLUSION: MLL/AF4 is the most common partner gene for 11q23/MLL gene rearrangement. This type of leukemia is mainly pro-B-ALL. Although conventional chemotherapy can achieve certain rate of remission, it is easy to relapse and the prognosis is very poor. Allo-HSCT may improve the prognosis.


Assuntos
Rearranjo Gênico , Transplante de Células-Tronco Hematopoéticas , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Estudos Retrospectivos
20.
PLoS Pathog ; 16(9): e1008813, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925973

RESUMO

HIV Nef counteracts cellular host restriction factors SERINC3 and SERINC5, but our understanding of how naturally occurring global Nef sequence diversity impacts these activities is limited. Here, we quantify SERINC3 and SERINC5 internalization function for 339 Nef clones, representing the major pandemic HIV-1 group M subtypes A, B, C and D. We describe distinct subtype-associated hierarchies for Nef-mediated internalization of SERINC5, for which subtype B clones display the highest activities on average, and of SERINC3, for which subtype B clones display the lowest activities on average. We further identify Nef polymorphisms that modulate its ability to counteract SERINC proteins, including substitutions in the N-terminal domain that selectively impair SERINC3 internalization. Our findings demonstrate that the SERINC antagonism activities of HIV Nef differ markedly among major viral subtypes and between individual isolates within a subtype, suggesting that variation in these functions may contribute to global differences in viral pathogenesis.


Assuntos
Infecções por HIV/virologia , HIV-1/fisiologia , Glicoproteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/antagonistas & inibidores , Polimorfismo Genético , Replicação Viral , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo , Infecções por HIV/genética , Infecções por HIV/metabolismo , Soropositividade para HIV , Interações Hospedeiro-Patógeno , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Células Tumorais Cultivadas , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética
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