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This study aimed to investigate the relationship between anomalous DNA nucleotidylexotransferase (DNTT) activation and the mutagenesis of gene length mutations (LMs) in acute myeloid leukemia (AML), and the relevance of their prognosis in antithymocyte globulin (ATG)-based regimen allogeneic hematopoietic stem cell transplantation (allo-HSCT). A cohort of 578 AML cases was enrolled. Next-generation sequencing was performed to screen mutations of 86 leukemia driver genes. RNA-seq was used to analyze gene expression. Prognostic analysis was investigated in 239 AML cases who underwent ATG-based regimen allo-HSCT. We report a refined subtyping algorithm of LMs (type I-IV) based on sequence anatomy considering the TdT-aided mutagenesis mechanism. GC content adjacent to LM junctions, inserted nontemplate nucleotide bases, and DNTT expression analysis supported the DNTT activation and TdT-aided mutagenesis in type II/III LMs in the total AML cohort. Both single-variate and multivariate analyses showed a better overall survival of FLT3 type III compared to type I in a subset of ATG-based regimen allo-HSCT cases. The novel LM subtyping algorithm not only deciphers the etiology of the mutagenesis of LMs but also helps to fine-tune prognosis differentiation in AML. The possible prognostic versatility of this novel LM subtyping algorithm in terms of chemotherapy, targeted therapy, and allo-HSCT merits further investigation.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , DNA Nucleotidilexotransferase/genética , Soro Antilinfocitário/genética , Soro Antilinfocitário/uso terapêutico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Estudos RetrospectivosRESUMO
The cell cycle is governed by stringent epigenetic mechanisms that, in response to intrinsic and extrinsic regulatory cues, support fidelity of DNA replication and cell division. We will focus on (1) the complex and interdependent processes that are obligatory for control of proliferation and compromised in cancer, (2) epigenetic and topological domains that are associated with distinct phases of the cell cycle that may be altered in cancer initiation and progression, and (3) the requirement for mitotic bookmarking to maintain intranuclear localization of transcriptional regulatory machinery to reinforce cell identity throughout the cell cycle to prevent malignant transformation.
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Epigênese Genética , Neoplasias , Humanos , Ciclo Celular/genética , Divisão Celular , Neoplasias/genética , Neoplasias/patologia , Cromatina , Regulação da Expressão GênicaRESUMO
Epigenetic gene regulatory mechanisms play a central role in the biological control of cell and tissue structure, function, and phenotype. Identification of epigenetic dysregulation in cancer provides mechanistic into tumor initiation and progression and may prove valuable for a variety of clinical applications. We present an overview of epigenetically driven mechanisms that are obligatory for physiological regulation and parameters of epigenetic control that are modified in tumor cells. The interrelationship between nuclear structure and function is not mutually exclusive but synergistic. We explore concepts influencing the maintenance of chromatin structures, including phase separation, recognition signals, factors that mediate enhancer-promoter looping, and insulation and how these are altered during the cell cycle and in cancer. Understanding how these processes are altered in cancer provides a potential for advancing capabilities for the diagnosis and identification of novel therapeutic targets.
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Epigênese Genética , Neoplasias , Humanos , Fenótipo , Neoplasias/genética , Neoplasias/patologia , Regulação da Expressão Gênica , CromatinaRESUMO
Whether Fanconi anemia (FA) heterozygotes are predisposed to bone marrow failure and hematologic neoplasm is a crucial but unsettled issue in cancer prevention and family consulting. We retrospectively analyzed rare possibly significant variations (PSVs) in the five most obligated FA genes, BRCA2, FANCA, FANCC, FANCD2, and FANCG, in 788 patients with aplastic anemia (AA) and hematologic malignancy. Sixty-eight variants were identified in 66 patients (8.38%). FANCA was the most frequently mutated gene (n = 29), followed by BRCA2 (n = 20). Compared with that of the ExAC East Asian dataset, the overall frequency of rare PSVs was higher in our cohort (P = 0.016). BRCA2 PSVs showed higher frequency in acute lymphocytic leukemia (P = 0.038), and FANCA PSVs were significantly enriched in AA and AML subgroups (P = 0.020; P = 0.008). FA-PSV-positive MDS/AML patients had a higher tumor mutation burden, higher rate of cytogenetic abnormalities, less epigenetic regulation, and fewer spliceosome gene mutations than those of FA-PSV-negative MDS/AML patients (P = 0.024, P = 0.029, P = 0.024, and P = 0.013). The overall PSV enrichment in our cohort suggests that heterozygous mutations of FA genes contribute to hematopoietic failure and leukemogenesis.
Assuntos
Anemia Aplástica , Anemia de Fanconi , Neoplasias Hematológicas , Leucemia Mieloide Aguda , Anemia Aplástica/genética , Epigênese Genética , Anemia de Fanconi/genética , Células Germinativas , Neoplasias Hematológicas/genética , Humanos , Leucemia Mieloide Aguda/genética , Estudos RetrospectivosRESUMO
BACKGROUND: The anti-cancer effect of vitamin C (VC) has long been speculated, but studies yielded inconsistency. Recent studies reported that supraphysiological concentration of VC have therapeutic or prevention effects for myeloid malignancies with certain mutation signatures. There was a notable proportion of DAT (i.e., DNMT3A, ASXL1, and TET2) and dozens of other genes that mutate in age-related clonal hematopoiesis (ARCH). METHODS AND RESULTS: Through analyzing the plasma VC concentration and mutations of 21 genes in 215 senior volunteers, we revealed that ARCH is significantly associated with dietary plasma VC concentrations, especially TET2 mutations and non-DAT mutations. CONCLUSION: This study firstly disclosed the significant association between VC inadequacy and ARCH in the senior population. It provides evidence that physiological VC concentration has ARCH prevention effect. It will illuminate future explorations on the oral VC supplement in maintaining sound hematopoiesis, reversal ARCH, adjuvant therapy for myeloid malignancies, and prevention of other ARCH related comorbidities.
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Ácido Ascórbico , Hematopoiese Clonal , Hematopoese/genética , Humanos , MutaçãoRESUMO
AIM: This study aimed to investigate the regularity of gene mutations in patients with myelodysplastic syndrome (MDS) and in those that progressed to acute myeloid leukemia (MDS/AML). PATIENTS & METHODS: High-throughput sequencing technology was used to detect gene mutations in 99 newly diagnosed patients with MDS or MDS/AML. RESULTS: Gene mutations were detected in 88 patients. The mutation incidence in the MDS/AML group was significantly higher than that in the MDS group. Statistically significant differences were observed between the MDS with refractory anemia (MDS-RA) and MDS-RA with excess blasts groups and between the MDS/AML and MDS-RA groups. CONCLUSION: Our data demonstrate that there is a cumulative accumulation of gene mutations, especially in transcription factor genes, during disease progression in MDS and MDS/AML.
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Graft-versus-host disease (GVHD) is a critical complication after allogeneic haematopoietic stem cell transplantation induced by genetic differences in donor-recipient pairs. Rigorous HLA matching has reduced GVHD, but severe GVHD still occurs. Minor histocompatibility antigens (mHAs) are another source of GVHD inducers. We designed a multi-mHA panel with 35 valid mHA loci and retrospectively analyzed 391 donor-recipient pairs with the anticipation of implementing mHA typing into clinical practice to optimize donor selection. Results showed the total mismatching in mHA loci in this panel, as well as mismatching in the GVH direction in unmatched-related recipients (UMRs) were 1.8 times and 1.3 times as those in matched-sibling recipients (MSRs) (p = 4.1e-4, p = 0.012, respectively). There was no significant association between mHA loci mismatching and grades II-IV acute GVHD (aGVHD), III-IV aGVHD, extensive chronic GVHD (cGVHD), or relapse in neither group. UMRs had an increased cumulative incidence of II-IV aGVHD (p = 0.002), but there was no statistical difference of the incidences in severe aGVHD or cGVHD (p = 0.093; p = 0.930). This is a preliminary study to explore GVHD risks brought by mHA loci mismatching in both unmatched-related recipients and matched-full-sibling recipients. Our results confirmed that stringent HLA matching is the key to reduce the risks for GVHD.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Histocompatibilidade , Teste de Histocompatibilidade , Humanos , Antígenos de Histocompatibilidade Menor/genética , Estudos Retrospectivos , IrmãosRESUMO
OBJECTIVE: To detect fusion gene with pathological significance in a patient with refractory and relapsed acute B cell lymphoblastic leukemia (B-ALL) and to explore its laboratory and clinical characteristics. METHODS: Transcriptome sequencing was used to detect potential fusion transcripts. Other laboratory results and clinical data of the patient were also analyzed. RESULTS: The patient was found to harbor TCF3 exon 17-ZNF384 exon 7 in-frame fusion transcript. The minimal residual disease (MRD) has remained positive after multiple chemotherapy protocols including CD19-, CD22- targeted chimeric antigen receptor T cells immunotherapy. The patient eventually achieved complete remission and sustained MRD negativity after allogeneic hemopoietic stem cell transplantation (allo-HSCT). CONCLUSION: Transcriptome sequencing can effectively detect potential fusion genes with clinical significance in leukemia. TCF3-ZNF384 positive B-ALL has unique laboratory and clinical characteristics, may not well respond to chemotherapy and immunotherapy, and is more likely to relapse. Timely allo-HSCT treatment may help such patients to achieve long-term disease-free survival. TCF3-ZNF384 positive B-ALL is not uncommon in pediatric patients but has not been effectively identified.
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Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Linfócitos B , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Criança , Humanos , Laboratórios , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transativadores/genética , TranscriptomaAssuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Leucemia Mieloide Aguda/genética , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Biomarcadores Tumorais , Humanos , Leucemia Mieloide Aguda/diagnósticoRESUMO
BACKGROUND: Fanconi anemia (FA) is the most common inherited bone marrow failure (BMF) syndrome with 22 related genes identified. The ALDH2 rs671variant has been proved related to accelerate the progression of BMF in FA patients. The phenotype and genetic basis of Chinese FA patients have not been investigated yet. METHODS: We analyzed the 22 FA-related genes of 63 BMF patients suspected to be FA. Clinical manifestations, morphological and cytogenetic feathers, ALDH2 genotypes, treatment, and outcomes of the definite cases were retrospectively studied. RESULTS: A total of 21 patients were confirmed the diagnosis of FA with the median age of BMF onset was 4-year-old. The number of patients manifested as congenital malformations and growth retardation were 20/21 and 14/21, respectively. BM dysplasia and cytogenetic abnormalities were found in 13/20 and 8/19 patients. All the patients with abnormal karyotypes also manifested as BM dysplasia or had evident blasts. Thirty-five different mutations were identified involving six genes and including twenty novel mutations. FANCA mutations contributed to 66.67% of cases. Eight patients harboring ALDH2-G/A genotype have a significantly younger age of BMF onset (p = 0.025). Within the 19 patients adhering to continuous follow-up, 15 patients underwent hematopoietic stem cell transplantations (HSCTs). During the 29 months of follow-up, 8/19 patients died, seven of which were HSCT-related, and one patient who did not receive HSCT died from severe infection. CONCLUSIONS: The phenotypic and genetic spectrum of Chinese FA patients is broad. Bone marrow dysplasia and cytogenetic abnormalities are prevalent and highly consistent. The overall outcome of HSCTs is disappointing. Nationwide multicenter studies are needed for the rarity and adverse outcome of this disease.
Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Estudos de Associação Genética , Genótipo , Mutação , Fenótipo , Adolescente , Medula Óssea/patologia , Criança , Pré-Escolar , Quebra Cromossômica , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Cariótipo , MasculinoRESUMO
OBJECTIVE: To develop an automated chimeric analysis and reporting platform based on short tandem repeat (STR) and capillary electrophoresis methods for allogeneic hematopoietic stem cell transplantation (allo-HSCT) so as to improve work efficiency. METHODS: Apache, MySQL, PHP and HTML5 were used to build the database and interface. The STR locus geno typing and chimeric analysis logic and flow were set up on the basis of STR rules and capillary electrophoresis. STR genotyping and 194 times of chimeric testing data of 100 patients after allo-HSCT were used to test the platform for automatic STR locus genotyping, chimeric calculation and report generation. RESULTS: The established platform could realize the functions of STR locus customization, STR genotype determination, automatic chimeric analysis, and detection information database management, which can automatically generate an integrated report including multiple sequential chimeric results and trend graphs for the same patient and can be accessed and used simultaneously by different users through different browser interfaces. The results of automated analysis by the platform are completely consistent with that of manual analysis by experienced technicians, and the possibility of manual analysis error is reduced through automation. The time required for automatic analysis using this platform is approximately 1/6-1/5 of manual analysis. CONCLUSION: The automatic analysis platform built in this study is operation stable and reliable in analysis results, which can improve work efficiency and report connotation, thus worthing popularized and applicable.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Eletroforese Capilar , Genótipo , Humanos , Repetições de Microssatélites , Doadores de TecidosAssuntos
Síndrome de Bloom/complicações , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas de Ligação a DNA/genética , Transplante de Células-Tronco Hematopoéticas , Leucemia Monocítica Aguda/terapia , Proteínas de Fusão Oncogênica/genética , Terapia de Salvação , Fatores de Transcrição/genética , Cariótipo Anormal , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sequência de Bases , Síndrome de Bloom/genética , Criança , Resistencia a Medicamentos Antineoplásicos , Éxons/genética , Heterozigoto , Humanos , Leucemia Monocítica Aguda/tratamento farmacológico , Leucemia Monocítica Aguda/etiologia , Leucemia Monocítica Aguda/genética , Masculino , Domínios Proteicos , Indução de Remissão , Sequenciamento do ExomaRESUMO
Chromosome translocation t(12;22)(p13;q12)/MN1-ETV6 and MN1 overexpression confer a subset of adverse prognostic AML but so far lack in-depth research. We focused on the clinical course and comprehensive genetic analysis of eight cases with t(12;22)(p13;q12) and one with t(12;17;22) (p13;q21;q13) to elucidate their molecular etiology and outcomes of allogeneic hemopoietic stem cell transplantation (allo-HSCT). The total incidence of t(12;22)(p13;q12) and related translocations was 0.32% in myeloid neoplasms. These patients were confirmed to have dismal prognosis when treated only with chemotherapy, and we firstly provided evidence that they can significantly benefit from timely allo-HSCT. Five cases were MN1-ETV6 positive, and a novel MN1-STAT3 fusion was identified in the patient with triadic translocation. Significant MN1 overexpression was observed in all three MN1-fusion-negative cases. Genetic analysis highlighted the evidence of an ectopic super-enhancer associated orchestrated mechanism of MN1 overexpression and ETV6 haploinsufficiency in t(12;22)(p13;q12) myeloid neoplasms, rather than the conventional thought of MN1-ETV6 fusion formation. We also disclosed the high concomitance of trisomy 8 and 531 Kbps focal 8q duplication in t(12;22)(p13;q12) cases. The new perspective about this entity of disease will enlighten further research to define the mechanism of tumorigenesis and discover effective treatments for MN1-driven malignancies.
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Genômica/métodos , Síndromes Mielodisplásicas/genética , Transativadores/uso terapêutico , Fatores de Transcrição/genética , Translocação Genética/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transativadores/farmacologia , Proteínas Supressoras de Tumor/farmacologia , Proteínas Supressoras de Tumor/uso terapêutico , Adulto JovemAssuntos
Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Imidazóis/administração & dosagem , Leucemia/tratamento farmacológico , Leucemia/genética , Mutação , Piridazinas/administração & dosagem , Adulto , Criança , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Acute myeloid leukemia (AML) with double mutant CEBPA (CEBPAdm) is generally associated with favorable prognosis, but the heterogeneity still blatant and needs further exploration. We aimed to comprehensively analyze the companion genetic abnormalities and their clinical significance in AML patients with CEBPAdm. By performed targeted amplicon sequencing of 58 genes in specimens at the time of initial diagnosis of 609 AML patients, we identified 76 cases (12.5%) were CEBPAdm, and 88.2% of them also carry other gene mutations. There were more additional gene mutations, especially more epigenetic modifiers gene mutations in CEBPAsm than CEBPAdm cases, while GATA2, CSF3R, JAK3, and KIT mutations were exclusively betide in CEBPAdm but not CEBPAsm. Mutations of tyrosine kinase genes confer to adverse prognostic in karyotype normal CEBPAdm AML and provide potential therapeutic targets. The incidence of germline CEBPA mutation in CEBPAdm cases was 5.3% (4/76), including one C-terminal mutation. Deciphering the mutation spectrum of CEBPAdm AML could facilitate an in-depth understanding of the pathogenesis and refine the prognostic classification of this disease entity.
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Proteínas Estimuladoras de Ligação a CCAAT , Leucemia Mieloide Aguda/genética , Mutação , Adolescente , Adulto , Idoso , Povo Asiático/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Recurrent fusion genes (FGs) with clinical significances in leukemias are mainly mutually exclusive, and the coexistence of different FGs has been rarely reported. In this study, we retrospectively analyzed the incidence, genetic characteristics, and prognosis of leukemias with concurrent pathogenic FGs, which commonly reported in hematological malignancies in 8226 leukemia patients. A total of 25 patients with coexistence of double FGs were identified, accounting for 0.30% of all cases enrolled. More than half of the cases (14/25, 56%) were diagnosed as chronic myeloid leukemia in accelerated or blast phase, another six and five cases were acute myeloid leukemia and acute lymphocytic leukemia, respectively. Most cases (20/25, 80%) carried constitutively activated tyrosine kinases FGs (BCR-ABL1 or ETV6-PDGFRB) and transcription factors associated FGs simultaneously. Of the 11 patients with contemporaneous karyotype, 5 (45%) showed visible chromosomal abnormalities corresponding to both FGs. The concurrency of FGs was often associated with disease progressions. The prognosis was pessimistic for patients with concurrent FGs, even with the combination of targeted therapy and chemotherapy. Performing allogeneic hematopoietic stem cell transplantation as soon as possible after complete remission can ameliorate the dismal prognosis.
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Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Criança , Progressão da Doença , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Incidência , Cariotipagem/estatística & dados numéricos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome with 22 FA-related genes identified to date. Fragment deletions are frequently occurring aberrances accounting for ~30% of pathogenic variants in them, especially in FANCA, most of which are the results of genomic rearrangement events mediated by the highly concentrated Alu elements interspersing in it. Owing to the capability to detect genome-wide copy number variations (CNVs) with the resolution of 400 kb or larger, cytogenomic microarray is the most widely used method in the clinic currently. However, thereis still a technical gap in the detection of CNVs ranging from hundreds of bp to hundreds of kb between microarray, Sanger sequencing, and direct targeted high-throughput sequencing (THS). Here, we report the analysis of overlapping heterozygous novel submicroscopic deletions of FANCA gene in a FA patient, and discuss the mechanism of the deletions and the formation of FANCA-VPS9D1 fusion transcripts. Our results support that both low-coverage whole-genome sequencing and bioinformatics analysis of THS data for submicroscopic CNVs surpass SNP array in efficacy and accuracy.
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Variações do Número de Cópias de DNA , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Fusão Gênica , Heterozigoto , RNA Longo não Codificante/genética , Criança , Humanos , MasculinoRESUMO
The RARG gene is a member of the nuclear hormone receptor superfamily and shares high homology with RARA and RARB. RARA is involved in translocation with PML in acute promyelocytic leukaemia (APL). Little is known about RARB or RARG rearrangement. RARG fusions were reported in only five APL patients and the partner genes were NUP98, PML and CPSF6. Here, we report NPM1 as a new partner gene of RARG and identify a unique NPM1-RARG-NPM1 chimeric fusion for the first time in an old male with morphological and immunophenotypical features of hypergranular APL but lacking response to all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) therapy. The structural features of the fusion transcript may account for the clinical resistance of the patient. RARG fusion is rare but recurrent in APL, further investigation in larger cohorts is expected to assess frequency, clinical characteristics and outcomes of RARG-translocation in APL.
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Trióxido de Arsênio/uso terapêutico , Fusão Gênica , Leucemia Mieloide Aguda/genética , Leucemia Promielocítica Aguda/genética , Proteínas Nucleares/genética , Receptores do Ácido Retinoico/genética , Tretinoína/uso terapêutico , Idoso , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Nucleofosmina , Receptor gama de Ácido RetinoicoRESUMO
Mucus hypersecretion is the key manifestation in patients with chronic inflammatory airway diseases and mucin 5AC (MUC5AC) is a major component of airway mucus. Matrix metalloproteinases (MMP)-9, have been found to be involved in the pathogenesis of inflammatory airway diseases. Hyperglycemia has been shown to be an independent risk factor for respiratory infections. We hypothesize that high glucose (HG)-regulates MMP-9 production and MMP-9 activity through nicotinamide adenine dinucleotide phosphate (NADPH)/reactive oxygen species (ROS) cascades pathways, leading to mucin production in human airway epithelial cells (16HBE). We show that HG increases MMP-9 production, MMP-9 activity and MUC5AC expression. These effects are prevented by small interfering RNA (siRNA) for MMP-9, indicating that HG-induced mucin production is MMP-9-dependent. HG activates MMP-9 production, MMP-9 activity and MUC5AC overproduction, which is inhibited by nPG, DMSO and DPI (inhibitors of ROS and NADPH), suggesting that HG-activated mucin synthesis is mediated by NADPH/ROS in 16HBE cells. These observations demonstrate an important role for MMP-9 activated by NADPH/ROS signaling pathways in regulating HG-induced MUC5AC expression. These findings may bring new insights into the molecular pathogenesis of the infections related to diabetes mellitus and lead to novel therapeutic intervention for mucin overproduction in chronic inflammatory airway diseases.