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1.
Mol Med Rep ; 21(2): 883-893, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31789407

RESUMO

Rearrangement of the mixed lineage leukemia (MLL; also known as lysine methyltransferase 2A) gene is a recurrent genomic aberration in acute myeloid leukemia (AML). MLLT3, super elongation complex subunit (AF9) is one of the most common MLL fusion partners in AML. The present study aimed to explore the aberrant expression of genes associated with the MLL­AF9 translocation and identified potential new targets for the therapy of AML with MLL­AF9 translocation. The transcriptomic and epigenetic datasets were downloaded from National Center of Biotechnology Information Gene Expression Omnibus (GEO) database. Differentially expressed genes were obtained from two independent datasets (GSE68643 and GSE73457). Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery. MLL­AF9­associated chromatin immunoprecipitation sequencing (ChIP­Seq) data was analyzed and identified binding sites for MLL­AF9 and wild type MLL (MLL WT). The ChIP­Seq of histone modification data was downloaded from the GEO database, including histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 79 dimethylation (H3K79me2) and histone 3 lysine 27 acetylation (H3K27ac), was used for comparing histone modification marks between the MLL­AF9 leukemia cells and normal hematopoietic cells at MLL­AF9 and MLL WT binding sites. The differentially expressed genes with the same trend in H3K79me2, H3K27ac and H3K4me3 alteration were identified as potential MLL­AF9 direct target genes. Upon validation using RNA­Seq data from the Therapeutically Applicable Research to Generate Effective Treatments AML project, eight potential direct target genes of MLL­AF9 were identified and further confirmed in MLL­AF9 mouse model using reverse transcription­quantitative polymerase chain reaction. These genes may have a critical role in AML with MLL­AF9 translocation.

2.
Oncol Rep ; 42(6): 2426-2434, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638261

RESUMO

RAD51, is a key homologous recombination protein that repairs DNA damage and maintains gene diversity and stability. Previous studies have demonstrated that the over­expression of RAD51 is associated with chemotherapy resistance of tumor cells to chemotherapy, and enhanced activity of DNA damage repair (DDR) systems contributes to resistance of adult T­cell leukemia­lymphoma (ATL) resistance to chemotherapy. Thus, targeting RAD51 is a potential strategy for the sensitization of ATL cells to chemotherapeutic drugs by inducing DNA damage. In general, cells can repair minor DNA damage through DDR; however, serious DNA damage may cause cell toxicity in cells which cannot be restored. In the present, down regulation of RAD51 by shRNA and imatinib sensitized Jurkat cells to etoposide by decreasing the activity of homologous recombination (HR). We found that the suppression of RAD51 by shRNA inhibited tumor cells proliferation and enhanced apoptosis of Jurkat cells after etoposide treatment. Importantly, downregulation of RAD51 by imatinib obviously increased the apoptosis of Jurkat cell after etoposide treatment. These results demonstrated that RAD51 may be of great value to as a novel target for the clinical treatment of adult T­cell leukemia­lymphoma (ATL), and it may improve the survival of leukemia patients.

3.
Adv Exp Med Biol ; 1143: 147-171, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31338819

RESUMO

In humans, hematopoietic stem cells (HSCs) adopt unique responsive pathways counteracting with the DNA-damaging assaults to weigh the balance between the maintenance of normal stem cell poor for whole-life blood regeneration and the transformation to leukemia stem cells (LSCs) for leukemia initiation. LSCs also take actions of combating with the attack launched by externally therapeutic drugs that can kill most leukemic cells, to avoid extermination and promote disease relapse. Therefore, the collection of knowledge about all these underlined mechanisms would present a preponderance for later studies. In this chapter, the universal DNA damage response (DDR) mechanisms were firstly introduced, and then DDR of HSCs were presented focusing on the DNA double-strand breaks in the quiescent state of HSCs, which poses a big advantage in promoting its transformation into preleukemic HSCs. Lastly, the DDR of LSCs were summarized based on the major outcomes triggered by different pathways in specific leukemia, upon which some aspects for future investigations were envisioned under our currently limited scope of knowledge.


Assuntos
Dano ao DNA , Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Células-Tronco Neoplásicas , Divisão Celular , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/patologia
4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(2): 504-508, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-30998161

RESUMO

OBJECTIVE: To explore the potential pathogenetic mutations of primary hypereosinophilia(HEN)by sequencing FGFR1 FLT3, MPL and JAK2 genes, and to clarify their effect on clinical manifestation and prognosis of HEN patients. METHODS: The direct DNA sequencing was employed to detect the gene mutations of FGFR1, FLT3, MPL and JAK2 in HEN patients. RESULTS: One deletion mutation (2654_2753del) within tyrosine kinase domain of FLT3 gene was found in a patient suffered from severe symptoms and ended with dismal outcome, which induced a premature stop codon (G885fsX888). For FGFR1, a new variation described as 1014_1019del AACAGT for nucleotide change was found in 19 cases, resulting in T339_V340del at the protein level. CONCLUSION: The deletion of 6 bases in the FGFR1 gene (1014_1019del AACAGT) is first reported as non-synonymous SNP (nsSNP) site in the patients with primary hypereosinophilia. Deletion mutations in the FLT3 gene may be related with malignant clinical features and poor prognosis.


Assuntos
Síndrome Hipereosinofílica/genética , Mutação , Sequência de Bases , Humanos , Receptores de Trombopoetina , Deleção de Sequência , Tirosina Quinase 3 Semelhante a fms
6.
Cell Physiol Biochem ; 49(6): 2111-2123, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30273928

RESUMO

BACKGROUND/AIMS: T-Cell Acute Lymphoblastic Leukemia (T-ALL) [corrected] is an aggressive disease which is highly resistant to chemotherapy. Studies show that enhanced ability of DNA damage repair (DDR) in cancer cells plays a key role in chemotherapy resistance. Here, we suggest that defect in DDR related genes might be a promising target to destroy the genome stability of tumor cells. METHODS: Since KU70 is highly expressed in Jurkat cells, one of the most representative cell lines of ATL, we knocked down KU70 by shRNA and analyzed the impact of KU70 deficiency in Jurkat cells as well as in NOD-SCID animal models by western blot, immunofluorescence, flow cytometry and measuring DNA repair efficiency. RESULTS: It is observed that silencing of KU70 resulted in accumulated DNA damage and impaired DDR in Jurkat cells, resulting in more apoptosis, decreased cell proliferation and cell cycle arrest. DNA damage leads to DNA double-strand breaks (DSBs), which are processed by either non-homologous end joining(NHEJ) or homologous recombination(HR). In our study, both NHEJ and HR are impaired because of KU70 defect, accompanied with increased protein level of SHP-1, a dephosphorylation enzyme. In turn, SHP-1 led to dephosphorylation of SIRT1, which further impaired HR repair efficiency. Moreover, KU70 deficiency prolonged survival of Jurkat-xenografted mice. CONCLUSION: These findings suggest that targeting KU70 is a promising target for ATL and might overcome the existing difficulties in chemotherapy.


Assuntos
Reparo do DNA por Junção de Extremidades , Autoantígeno Ku/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Reparo de DNA por Recombinação , Sirtuína 1/metabolismo , Animais , Apoptose , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Pontos de Checagem do Ciclo Celular , Quebras de DNA de Cadeia Dupla , Humanos , Células Jurkat , Autoantígeno Ku/antagonistas & inibidores , Autoantígeno Ku/genética , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/metabolismo , Leucemia-Linfoma de Células T do Adulto/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fosforilação , Proteína Tirosina Fosfatase não Receptora Tipo 6/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Interferência de RNA , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/uso terapêutico , Rad51 Recombinase/metabolismo
7.
J Exp Clin Cancer Res ; 37(1): 204, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30157922

RESUMO

BACKGROUND: Considerable efforts have been devoted toward the uncovering of the molecular mechanisms underlying the maintenance of hematopoietic stem cells (HSCs) by the normal bone marrow (BM) niche. Previously, we demonstrated that a chemotherapy-induced niche, which is mainly composed of mesenchymal stem cells (MSCs), protects the residual B-cell acute lymphoblastic leukemia (B-ALL) cells from the insult of chemotherapeutic drugs. However, the roles of chemotherapy-induced niche on HSCs functions in B-ALL remain unclear. METHODS: We established an oncogenic N-MYC-driven B-ALL mouse model, which were subsequently treated with common chemotherapy drug cytarabine (Ara-C) and daunorubicin (DNR). After treatment, the structures of the BM niche were imaged by immunofluorescence staining. Then, the self-renewal and differentiation capability of the MSCs in the BM after Ara-C and DNR treatment were studied by ex vivo culture and gene expression analysis with RNA-seq and qRT-PCR. The effects of chemotherapy-induced niche on the hematopoietic reconstitution of HSCs were determined with series transplantation assay. Furthermore, the cell cycle, ROS level, mitochondrial membrane potential and cell apoptosis of HSCs were detected by flow cytometry. RESULTS: The MSCs, which is the main component of chemotherapy-induced BM niche, have decreased self-renewal capability and are prone to differentiate into adipocytes and chondrocytes. The results of gene expression analysis with RNA-seq showed that the MSCs have reduced levels of cytokines, including SCF, CXCL12, ANGPT1, VCAM1, and IL7. Furthermore, the chemotherapy-induced niche perturbed the hematopoietic reconstitution of HSCs in our N-MYC-driven B-ALL mouse model by promoting HSCs to enter cell cycle and increasing intracellular ROS levels and mitochondrial membrane potential of HSCs, which lead to the cell apoptosis of HSCs. CONCLUSIONS: Chemotherapy-induced BM niche perturbs the hematopoietic reconstitution of HSCs by increasing intracellular ROS level and inducing cell apoptosis.


Assuntos
Citarabina/administração & dosagem , Células-Tronco Hematopoéticas/metabolismo , Proteína Proto-Oncogênica N-Myc/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Autorrenovação Celular/efeitos dos fármacos , Autorrenovação Celular/genética , Modelos Animais de Doenças , Citometria de Fluxo , Regulação Leucêmica da Expressão Gênica , Células-Tronco Hematopoéticas/patologia , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Espécies Reativas de Oxigênio/metabolismo , Nicho de Células-Tronco/genética
8.
Cell Physiol Biochem ; 48(2): 657-669, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30025390

RESUMO

BACKGROUND/AIMS: Alternative splicing and DNA damage exhibit cross-regulation, with not only DNA damage inducing changes in alternative splicing, but alternative splicing itself possibly modulating the DNA damage response (DDR). Sirt1, a prominent anti-aging player, plays pivotal roles in the DDR. However, few studies have examined alternative splicing with DNA damage in neural stem cells (NSCs) and, in essence, nothing is known about whether SIRT1 regulates alternative splicing. Hence, we investigated the potential involvement of Sirt1-mediated alternative splicing in the NSC DDR. METHODS: Genome-wide alternative splicing profiling was performed upon DNA damage induction and SIRT1 deletion. RESULTS: DNA damage caused genome-wide changes in alternative splicing in adult NSCs and Sirt1 deficiency dramatically altered DDR-related alternative splicing. In particular, extensive alternative splicing changes in DDR-related processes such as cell cycle control and DNA damage repair were observed; these processes were dramatically influenced by Sirt1 deficiency. Phenotypically, Sirt1 deficiency altered the proliferation and DNA repair of adult NSCs, possibly by regulating alternative splicing. CONCLUSION: SIRT1 helps to regulate alternative splicing, which itself affects the DDR of NSCs. Our findings provide novel insight into the mechanisms underlying the DDR in stem cells.


Assuntos
Reparo do DNA , Sirtuína 1/genética , Processamento Alternativo/efeitos da radiação , Animais , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Células Cultivadas , Dano ao DNA/efeitos da radiação , Ventrículos Laterais/citologia , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/efeitos da radiação , Radiação Ionizante , Sirtuína 1/deficiência , Sirtuína 1/metabolismo
9.
Mol Med Rep ; 18(2): 1473-1484, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29901168

RESUMO

Long non-coding RNAs (lncRNAs) are transcripts characterized by >200 nucleotides, without validated protein production. Previous studies have demonstrated that certain lncRNAs have a critical role in the initiation and development of acute myeloid leukemia (AML). In the present study, the subtype­specific lncRNAs in AML was identified. Following the exclusion of the subtype­specific lncRNAs, the prognostic value of lncRNAs was investigated and a three­lncRNA expression­based risk score [long intergenic non­protein coding RNA 926, family with sequence similarity 30 member A and LRRC75A antisense RNA 1 (LRRC75A­AS1)] was developed for AML patient prognosis prediction by analyzing the RNA­seq data of AML patients from Therapeutically Available Research to Generate Effective Treatments (TARGET) and The Cancer Genome Atlas (TCGA) projects. In the training set obtained from TARGET, patients were divided into poor and favorable prognosis groups by the median risk score. The prognostic effectiveness of this lncRNA risk score was confirmed in the validation set obtained from TCGA by the same cut­off. Furthermore, the lncRNA risk score was identified as an independent prognostic factor in the multivariate analysis. As further verification of the independent prognostic power of the lncRNA risk score, stratified analysis was performed by a cytogenetics risk group and revealed a consistent result. The prognostic predictive ability of the risk score was compared with the cytogenetics risk group by time­dependent receiver operating characteristic curves analysis. It was revealed that the combination of the lncRNA risk score and cytogenetics risk group provided a higher prognostic value than a single prognostic factor. The present study also performed co­expression analysis to predict the potential regulatory mechanisms of these lncRNAs in a cis/trans/competing endogenous RNA manner. The results suggested that LRRC75A­AS1 was highly associated with the target genes of transcription factors tumor protein 53 and ETS variant 6. Overall, these results highlighted the use of the three­lncRNA expression­based risk score as a potential molecular biomarker to predict the prognosis in AML patients.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide Aguda/genética , RNA Antissenso/genética , RNA Longo não Codificante/genética , Atlas como Assunto , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Cariotipagem , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Análise Multivariada , Prognóstico , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , RNA Antissenso/metabolismo , RNA Longo não Codificante/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Risco , Transdução de Sinais , Análise de Sobrevida , Transcriptoma , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
10.
Exp Ther Med ; 15(2): 1966-1974, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29434791

RESUMO

The present study aimed to evaluate the efficacy and safety of combined immunosuppressive therapy (IST) plus umbilical cord blood infusion (UCBI) in severe aplastic anemia (SAA) patients. A total of 68 patients with SAA were enrolled in the current prospective cohort study and divided into the IST (n=35; positive control) and IST+UCBI (n=33; experimental) groups according to the treatment conditions. Patients in the IST group were treated with rabbit antithymocyte globulin (r-ATG) at a dose of 2.5 mg/kg through intravenous infusion once a day for five days. This was combined with oral cyclosporine A (CsA) at a dose of 3-5 mg/kg twice a day for 2 years. Patients in the IST+UBCI group were treated with r-ATG and CsA at the same doses and frequencies as the IST group plus one UCBI 1 day after the final treatment with r-ATG. At 6 months post treatment, the complete response and overall response rate (ORR) of the IST+UCBI group were markedly higher compared with those in the IST group. Furthermore, patients in the IST+UCBI group achieved absolute neutrophil count (ANC) and platelet count responses more rapidly as compared with the IST group. However, no difference in the hemoglobin (Hb) response was identified between the two groups. In addition, SAA patients achieved responses in the ANC and platelet count more rapidly in comparison with very severe aplastic anemia (VSAA) patients, while the number of days to Hb responses were similar in the SAA and VSAA patients. Multivariate logistic regression analysis also revealed that IST+UCBI treatment was an independent predicting factor for patients achieving complete response or partial response, whereas VSAA was an independent predictor of a worse ORR. Platelet and reticulocyte were also independent predicting factors. Finally, the survival of patients was similar between the groups, and no difference in the safety of the treatment was observed. In conclusion, combined IST plus UCBI treatment may be applied as an effective and safe therapy for SAA patients.

11.
Oncotarget ; 8(46): 80531-80544, 2017 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-29113323

RESUMO

Idiopathic pulmonary fibrosis (IPF) and idiopathic nonspecific interstitial pneumonia (INSIP) are two related diseases involving varying degrees of pulmonary fibrosis with no effective cure. Bone morphogenetic protein 3 (BMP3) is a member of the transforming growth factor-ß (TGF-ß) super-family, which has not been implicated in pulmonary fibrosis previously. In this study, we aimed to investigate the potential role of BMP3 playing in pulmonary fibrosis from clinical diagnosis to molecular signaling regulation. RNA sequencing was performed to explore the potential biomarker of IIP patients. The expression of BMP3 was evaluated in 83 cases of IPF and INSIP by immunohistochemistry. The function of BMP3 was investigated in both fibroblast cells and a bleomycin-induced murine pulmonary fibrosis model. The clinical relevance of BMP3 expression were analyzed in 47 IIP patients, which were included in 83 cases and possess more than five-year follow-up data. Both RNA-sequencing and immunohistochemistry staining revealed that BMP3 was significantly down-regulated in lung tissues of patients with IPF and INSIP. Consistently, lower expression of BMP3 also was found in pulmonary fibrotic tissues of bleomycin-induced mice model. Up-regulation of BMP3 prevented pulmonary fibrosis processing through inhibiting cellular proliferation of fibroblasts as well as TGF-ß1 signal transduction. Finally, the relatively higher expression of BMP3 in IPF patients was associated with less/worse mortality. Intravenous injection of recombinant BMP3. Taken together, our results suggested that the low expression level of BMP3 may indicate the unfavorable prognosis of IPF patients, targeting BMP3 may represent a novel potential therapeutic method for pulmonary fibrosis management.

12.
Cell ; 169(5): 945-955.e10, 2017 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-28525759

RESUMO

Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT. Moreover, blood transcriptome profiling revealed that mutant monkeys resembled RTT patients in immune gene dysregulation. Taken together, the stark similarity in phenotype and/or endophenotype between monkeys and patients suggested that gene-edited RTT founder monkeys would be of value for disease mechanistic studies as well as development of potential therapeutic interventions for RTT.


Assuntos
Proteína 2 de Ligação a Metil-CpG/genética , Síndrome de Rett/genética , Animais , Encéfalo/fisiologia , Cromossomos Humanos X , Ritmo Circadiano , Modelos Animais de Doenças , Eletrocardiografia , Feminino , Edição de Genes , Humanos , Macaca fascicularis , Imagem por Ressonância Magnética , Masculino , Mutação , Dor , Síndrome de Rett/fisiopatologia , Sono , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/metabolismo , Transcriptoma
13.
Medicine (Baltimore) ; 96(15): e6398, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28403071

RESUMO

Latest study showed that a novel translocation between programmed cell death ligand 1 (PD-L1) (cluster of differentiation 274) and TP63 (tumor protein 63) can be found in diffuse large B-cell lymphoma (DLBCL), resulting in their conjunct overexpression in tumor cells at RNA level. However, the expressed pattern of these 2 genes at protein level in DLBCL remains largely unknown, and the clinical relevance of PD-L1 and TP63 expression in DLBCL are also unclear.Tumor tissues from 76 Chinese DLBCL patients were immunostained for programmed cell death 1 (PD-1), PD-L1, and TP63 using the EnVision system. Clinical relevance of PD-1, PD-L1, and TP63 in 74 DLBCL were analyzed by chi-square test, the Kaplan-Meier curves with log rank test, and Cox's proportional hazards regression model.PD-1 was mainly expressed in tumor-infiltrating lymphocytes (TILs) of 39.5% patients. PD-L1 was expressed in tumor cells of 26.3% patients, and TP63 was immunostained in nucleoli of tumor cells of 31.6% cases. PD-1 expression was significantly associated with the patients' gender and B symptoms (P = 0.032, P = 0.026). DLBCL with PD-L1 or TP63 expression in tumor cells showed low International Prognostic Index (IPI) score (P = 0.007, P = 0.009). PD-1 TILs was related to prolonged overall survival rate (OS) of DLBCL patients (P = 0.02), whereas PD-L1 expression was associated with worse clinical outcome of patients (P = 0.049). Immunoreactivity of TP63 was not correlated with patients' survival time. Besides, PD-1 expression, patients' age, Ann Arbor stage, and IPI score were significant prognostic markers for OS, but PD-L1 and TP63 had no prognostic significance.PD-1, PD-L1, and TP63 are frequently expressed in DLBCL. PD-1/PD-L1/TP63 blockade may be a potential therapeutic strategy for some patients.


Assuntos
Antígeno B7-H1/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Linfoma Difuso de Grandes Células B/genética , Receptor de Morte Celular Programada 1/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Tumorais/genética , Distribuição de Qui-Quadrado , China , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento
14.
Cancer Res ; 77(1): 164-174, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27784744

RESUMO

Myeloproliferative neoplasms such as polycythemia vera (PV), which are associated with the JAK mutation V617F, remain incurable despite progress in the use of JAK2 inhibitors for treatment of some of these diseases. In this study, we employed mice that undergo JAK2V617F-induced PV as a tool to explore new candidate targets for therapy. Our investigations focused on the lipid metabolic enzyme arachidonate 5-lipoxygenase (Alox5), which we found to be strongly upregulated by JAK2V617F in hematopoietic cells in vitro and in vivo Notably, genetic deletion of Alox5 or its inhibition in mice with a bioactive small-molecule inhibitor was sufficient to attenuate PV development. This therapeutic effect was associated with induction of a blockade in cell-cycle progression and also with apoptosis in PV cells. Genetic loss exerted an inhibitory effect on PV-initiating cells. Similarly, Alox5 inhibition was sufficient to suppress colony formation in human JAK2V617F-expressing CD34+ cells. Mechanistic investigations showed that Alox5 inhibition reduced AKT activation and decreased ß-catenin expression in JAK2V617F-expressing cells. Together, our results define Alox5 as a key genetic effector of JAK2V617F in driving PV, and they identify this enzyme as a candidate therapeutic target to treat this refractory myeloproliferative neoplasm. Cancer Res; 77(1); 164-74. ©2016 AACR.


Assuntos
Araquidonato 5-Lipoxigenase/genética , Janus Quinase 2/genética , Policitemia Vera/genética , Animais , Western Blotting , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Hidroxiureia/análogos & derivados , Hidroxiureia/farmacologia , Antagonistas de Leucotrienos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase
15.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 24(2): 510-4, 2016 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-27151020

RESUMO

OBJECTIVE: To evaluate the clinical efficacy and safety of decitabine and cyclosporine for treatment of low-risk and intermediate-risk-1 myelodysplastic syndrome (MDS) patients. METHODS: The clinical data of 27 cases of low risk and intermediate-risk-1 MDS during the past 3 years in Tongji hospital were analyzed retrospectively. These MDS patients were divided into 2 groups: decitabine group (11 cases) and cyclosporine group (16 cases). The MDS patients in the 2 groups were treated with ultra low dose of decitabine and cyclosporine A; the curetive efficacy and adverse reactions were evaluated. RESULTS: In the 11 patients with low-risk and intermediate-risk-1 MDS treated with 2 courses of ultra-low-dose decitabine, 4 cases (36.4%) achieved a hematological improvement, 7 cases (63.6%) showed ineffective, including non-remission in 6 cases (54.5 %) and death in 1 patient (9.1%), total effective rate were 36.4%; 3 cases died within the first year and the overall survival (OS) rate was 72.7%. The causes of death mainly were severe myelosuppression and the associated infection and bleeding. In the 16 patients with low-risk and intermediate-risk-1 MDS treated with cyclosporine (CsA), 10 cases (62.5%) achieved a hematological improvement, 6 cases (37.5%) showed ineffective, the total efficiency of 62.5%; no patients died within 1 year, the 1-year OS was 100%. Changes in neutrophils, hemoglobin and platelet were not significantly different between the two group. CONCLUSION: The clinical efficacy of decitabine on low-risk and intermediate-risk-1 MDS has not confirmed to be superior to cyclosporine (P = 0.252). However, the side effects of serious infection and myelosuppression were more severe in decitabine group than that in the cyclosporine group. Moreover, the 1-year overall survival rate in decitabine group is much lower than that in the cyclosporine group (P = 0.027). In regard to the small number of cases and short follow-up time in our this study, the more patients and longer follow-up time are needed to study.


Assuntos
Azacitidina/análogos & derivados , Ciclosporina/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Azacitidina/administração & dosagem , Azacitidina/uso terapêutico , Ciclosporina/administração & dosagem , Decitabina , Humanos , Pancitopenia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
16.
Tumour Biol ; 37(1): 531-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26227222

RESUMO

Treatment failure in cancer chemotherapy is largely due to the toxic effects of chemotherapeutic agents on normal cells/tissues. The proteasome inhibitor bortezomib has been successfully applied to treat multiple myeloma (MM), but there are some common adverse reactions in the clinic including peripheral neuropathy (PN). The TAK1 selective inhibitor 5Z-7-oxozeaenol has been widely studied in cancer therapy. Here, we investigated the potential synergy of bortezomib and 5Z-7-oxozeaenol in Burkitt's lymphoma (BL) cell lines. Cell viability assay showed that co-treatment of bortezomib at 8 nM, representing a one-eighth concentration for growth arrest, and 5Z-7-oxozeaenol at 2 µM, a dose that exhibited insignificant cytotoxic effects, synergistically induced apoptosis in the cell line Daudi. In parallel with the increasing dose of the bortezomib, and 5Z-7-oxozeaenol at 0.5 µM, lower colony formation efficiencies were seen in the cell line Daudi. Western blotting analysis verified that TAK1 inhibition by 5Z-7-oxozeaenol completely blocked JNK, p38, Erk, IKK, and IκB phosphorylation, which was almost instantly activated by TAK1 both directly or indirectly. Both agents synergistically prevented nuclear translocation of NF-κB, a characteristic of NF-κB inactivation. Moreover, a synergistic effect of bortezomib and 5Z-7-oxozeaenol on Western blotting analysis and flow cytometry was disclosed. Collectively, our results indicated that the proteasome inhibitor bortezomib and the TAK1 inhibitor 5Z-7-oxozeaenol displayed synergy on inhibiting BL cell apoptosis by inhibiting NF-κB activity.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Apoptose , Bortezomib/administração & dosagem , Linfoma de Burkitt/tratamento farmacológico , MAP Quinase Quinase Quinases/metabolismo , Zearalenona/análogos & derivados , Transporte Ativo do Núcleo Celular , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Citoplasma/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Inibidores Enzimáticos/química , Humanos , NF-kappa B/metabolismo , Inibidores de Proteassoma/administração & dosagem , Ratos , Zearalenona/administração & dosagem
17.
Oncotarget ; 7(12): 13538-50, 2016 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-26646449

RESUMO

Most chemotherapeutic agents for leukemia are DNA damaging agents. However, DNA lesions can be repaired by activities of DNA repair systems. Increasing evidence have shown that enhanced DNA damage repair capacity contributes to chemotherapy resistance in leukemia cells. Thus, targeting DNA repair mechanisms is a promising strategy for novel leukemia treatment. SIRT1 expressions were downregulated by lentivirus-delivered SIRT1 shRNA in myeloid leukemia cells. SIRT1 mRNA and protein levels were analyzed by real-time PCR and Western blot, respectively. Flow cytometry was carried out to analyze cell cycle progression, apoptosis and DNA damage repair efficiency. DNA damage levels were assessed by alkaline comet assay, and H2AX phosphorylation was analyzed by immunoblotting and immunofluorescence. A mouse leukemia model was established by transplanting lentivirus-infected K562 cells containing SIRT1 shRNA into sublethally irradiated NOD/SCID mice, and tumorigenesis was evaluated by detecting tumor weights and mice survival. SIRT1 expressions were upregulated in myeloid leukemic patients. Downregulation of SIRT1 by RNAi promoted etoposide-induced DNA damage in myeloid leukemia cells accompanied by reduced NHEJ activity, and increased Ku70 acetylation. Furthermore, SIRT1 knockdown resulted in cell cycle arrest, induction of apoptosis and reduction of K562 cell proliferation accompanied by enhanced p53 and FOXO1 acetylation in K562 cells after etoposide treatment. Importantly, SIRT1 downregulation reduced the tumorigenesis ability of K562 cells in mouse xenografts following chemotherapy treatment. These results revealed that SIRT1 promotes the NHEJ repair pathway by deacetylating Ku70 in K562 cells, suggesting that SIRT1 is a novel therapeutic target for treating myeloid leukemia.


Assuntos
Biomarcadores Tumorais/metabolismo , Dano ao DNA/genética , Reparo do DNA/genética , Autoantígeno Ku/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Sirtuína 1/metabolismo , Acetilação , Animais , Apoptose , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Ciclo Celular , Proliferação de Células , Ensaio Cometa , Feminino , Seguimentos , Humanos , Autoantígeno Ku/química , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Prognóstico , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Sci Rep ; 5: 17638, 2015 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-26627341

RESUMO

Patients with pulmonary fibrosis often have low vitamin D levels, the effects of which are largely unknown. We here report that early vitamin D supplementation significantly reduced the severity of pulmonary fibrosis and inflammatory cell accumulationin in the bleomycin-induced pulmonary fibrosis mouse model on supplementary days 14, 21 and 28 (P < 0.001). Vitamin D supplementation also prevented some ultrastructural changes in response to bleomycin administration, including basement membrane thickening, interstitial fibrin deposition and microvilli flattening or disappearance on days 14, 21 and 28, and lamellar body swelling or vacuolation on days 21 and 28. The bleomycin group had rising hydroxyproline level on days 14, 21 and 28, whereas the vitamin D treatment group showed consistently lower hydroxyproline level but still higher than that of the control group (P < 0.001). Our immunohistochemistry and densitometry analyses showed less staining for α-smooth muscle actin, a myofibroblast marker, in the vitamin D group compared to the bleomycin group (P < 0.001). Thus, vitamin D treatment could prevent bleomycin-induced pulmonary fibrosis by delaying or suppressing ultrastructural changes, as well as attenuating hydroxyproline accumulation and inhibiting myofibroblastic proliferation. These data further our understanding of the roles of vitamin D in pulmonary fibrogenesis and in the treatment of pulmonary fibrosis.


Assuntos
Bleomicina/efeitos adversos , Suplementos Nutricionais , Fibrose Pulmonar , Vitamina D/farmacologia , Animais , Bleomicina/farmacologia , Fibrina/metabolismo , Hidroxiprolina/metabolismo , Masculino , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fibrose Pulmonar/prevenção & controle
19.
Oncol Rep ; 34(6): 2935-42, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26398583

RESUMO

Most chemotherapy drugs used for the treatment of adult T-cell leukemia-lymphoma (ATL) cause cell death directly by inducing DNA damage, which can be repaired via several DNA repair pathways. Enhanced activity of DNA damage repair systems contributes to ATL resistance to chemotherapies. Targeting DNA repair pathways is a promising strategy for the sensitization of ATL cells to chemotherapeutic drugs. in the present study, inhibition of SIRT1 deacetylase by shRNA sensitized Jurkat cells to etoposide by reducing the activity of non-homologous end joining (NHEJ) and homologous recombination (HR). Silencing of SIRT1 deacetylase by shRNA resulted in enhanced apoptosis and cell cycle arrest, while reduced colony formation of Jurkat cells after etoposide treatment was accompanied by elevated acetylation of FOXO1. Furthermore, inhibition of SIRT1 led to decreased activity of DNA damage repair by NHEJ and HR, accompanied by increased Ku70 acetylation. Furthermore, SIRT1 downregulation prolonged the survival time of Jurkat-xenografted mice. These results suggested that SIRT1 promotes DNA double­strand repair pathways in Jurkat cells by deacetylating Ku70, and increases cell proliferation by deacetylating FOXO1. The results suggest that SIRT1 is a potential target for the development of combinatorial treatment for ATL.


Assuntos
Reparo do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia-Linfoma de Células T do Adulto/genética , Sirtuína 1/genética , Adulto , Animais , Antígenos Nucleares/genética , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Dano ao DNA/genética , Reparo do DNA por Junção de Extremidades/genética , Proteínas de Ligação a DNA/genética , Etoposídeo/administração & dosagem , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/genética , Recombinação Homóloga/genética , Humanos , Células Jurkat , Autoantígeno Ku , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/patologia , Camundongos , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/biossíntese , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Mol Clin Oncol ; 3(3): 730-736, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26161258

RESUMO

Colony-stimulating factors (CSF) have been widely used to prevent febrile neutropenia associated with chemotherapy. Due to the high intensity of chemotherapy in acute lymphoblastic leukemia (ALL), CSF as a crucial component of supportive care has played a significant role in the therapy. However, the effectiveness of CSF in treatment has not been identified by large clinical trials until now. The aim of the present study was to evaluate the effect of CSF on the long-term outcome of adult ALL patients. A comprehensive search strategy has been conducted, which covered the Cochrane Central Register of Controlled Trials, PubMed and Web of Science. The result includes seven randomized controlled trials containing a total of 753 patients. The administration of CSF significantly reduced the mortality at the end of the follow-up (RR, 0.85; 95% CI, 0.75-0.95), the mortality at day 30 (RR, 0.41; 95% CI, 0.23-0.74) and the number of patients with infection or severe infections (RR, 0.8; 95% CI, 0.7-0.9 and RR, 0.48; 95% CI, 0.3-0.75). The addition of CSF also marginally increased the number of patients achieving CR (RR, 1.14; 95% CI, 1.05-1.23). The use of CSF also shortened the duration of neutropenia (median days, 8-17 to 12.5-24). In conclusion, CSFs can be administered to ALL patients during myelosuppressive chemotherapy, particularly in the induction phase.

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