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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 40-50, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027251

RESUMO

OBJECTIVE: To investigate the correlation of single nucleotide polymorphisms (SNP) in arachidonate 5-lipoxygenase gene (ALOX5) rs2029253, rs2228064 and rs2228065 sites, 5-lipoxygenase activating protein gene (ALOX5AP) rs10507391, rs4769874 sites with the risk for genesis of adult myeloid leukemia. METHODS: By the approval from the hospital ethics committee and the informed consent of participants. 150 patients with myeloid leukemia (ML) as ML group and 134 healthy people as the control group were selected. The genomic DNA was extracted from the samples. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) combined with directly sequencing, PCR-amplified products were applied to test the polymorphism of 5 sites in ALOX5 and ALOX5AP gene. RESULTS: A allele frequencies of ALOX5 gene rs2029253 site in the ML group and the control group were 43.0% and 34.3%, respectively. And the G allele frequencies in the ML group and the control group were 57.0% and 65.7%, respectively. The genotype distributions of AA, AG and GG in ALOX5 gene rs2029253 site in the ML group were 32.2%, 21.5% and 46.3% respectively. That in the control group were 15.7%, 37.3% and 47.0% respectively. The genotype AA and A allele frequency of ALOX5 gene rs2029253 site were linked with the increased risk of myeloid leukemia (OR=2.26, 95% CI: 1.43-4.56, P<0.05; OR=1.44, 95% CI: 1.02-2.03, P<0.05). And the genotype AG and allele G reduced the susceptibility to myeloid leukemia (OR=0.46, 95% CI: 0.27-0.78, P<0.01; OR=0.69, 95% CI: 0.50-0.98, P<0.05), however, the polymorphisms of ALOX5 gene rs2228064 and rs2228065 site not correlated with the risk of myeloid leukemia (P>0.05). The A allele frequency of ALOX5AP gene rs10507391 site in the ML group and the control group were 30.7% and 36.2% respectirely. The genotype distribution rates of AA, AT and TT in ALOX5AP gene rs10507391 site in the ML group was 1.3%, 58.7% and 40.0% respectively, that in the control group were 9.7%, 53.0% and 37.3% respectively. The genotype AA of ALOX5AP gene rs10507391 site correlated with the decreased risk of myeloid leukemia (OR=0.13, 95% CI: 0.03-0.57, P<0.05), but the polymorphism of ALOX5AP gene rs4769874 site not correlated with the risk of myeloid leukemia (P>0.05). CONCLUSION: The genotype AA, AG and allele A, G of ALOX5 rs2029253, as well as ALOX5AP rs10507391 may be correlate with the susceptibility to myeloid leukemia.


Assuntos
Proteínas Ativadoras de 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/genética , Leucemia Mieloide , Adulto , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Leucemia Mieloide/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco
2.
Clin Sci (Lond) ; 134(2): 261-271, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31922199

RESUMO

Acute myeloid leukemia (AML) is a malignant disorder of hemopoietic stem cells. AML can escape immunosurveillance of natural killer (NK) by gene mutation, fusions and epigenetic modification. The mechanism of AML immune evasion is not clearly understood. Here we show that CD48 high expression is a favorable prognosis factor that is down-regulated in AML patients, which can help AML evade from NK cell recognition and killing. Furthermore, we demonstrate that CD48 expression is regulated by methylation and that a hypomethylating agent can increase the CD48 expression, which increases the NK cells killing in vitro. Finally, we show that CD48 high expression can reverse the AML immune evasion and activate NK cells function in vivo. The present study suggests that a combination the hypomethylating agent and NK cell infusion could be a new strategy to cure AML.


Assuntos
Antígeno CD48/imunologia , Epigênese Genética/imunologia , Inativação Gênica/imunologia , Leucemia Mieloide/imunologia , Evasão Tumoral/imunologia , Doença Aguda , Animais , Antimetabólitos Antineoplásicos/farmacologia , Antígeno CD48/genética , Linhagem Celular Tumoral , Células Cultivadas , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Metilação de DNA/imunologia , Decitabina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Estimativa de Kaplan-Meier , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/genética , Masculino , Camundongos Endogâmicos BALB C , Evasão Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Anticancer Res ; 39(9): 4757-4766, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519576

RESUMO

BACKGROUND/AIM: Azacitidine (AZA) is a hypomethylating agent used in myeloid neoplasms, however, approximately half of patients show treatment failure or relapse. This in vitro study investigated the effect of the combination of AZA with the natural compound curcumin (CUR) in increasing its efficacy. MATERIALS AND METHODS: We analyzed the effects of AZA plus CUR on proliferation, apoptosis, cell cycle and differentiation in myeloid leukemic cell lines (U-937, HL-60, K-562, and OCI-AML3) and bone marrow samples of patients. RESULTS: The results showed a synergy between AZA and CUR in all leukemic lines and in most leukemic samples, with a decrease in proliferation and an increase in apoptosis compared to the activity of each drug separately. In addition, AZA plus CUR showed low cytotoxicity in healthy samples. CONCLUSION: A remarkable antioncogenic effect of the combination of AZA plus CUR was shown, providing a basis for future studies analyzing the clinical efficacy of these drugs.


Assuntos
Antineoplásicos/farmacologia , Azacitidina/farmacologia , Curcumina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Feminino , Humanos , Leucemia Mieloide/genética , Masculino , Síndromes Mielodisplásicas/genética
4.
Blood Rev ; 37: 100587, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31400824

RESUMO

Clonal hematopoiesis (CH) as defined by the presence of somatic mutations in genes associated with myeloid neoplasms (MN) is common in healthy elderly individuals and does not necessarily constitute a premalignant state. Several acronyms (idiopathic cytopenia of undetermined significance [ICUS], clonal cytopenia of undetermined significance [CCUS], CH of indeterminate potential [CHIP]) related to CH have been coined to describe patients who do not meet the diagnostic criteria for other hematologic disorders. CHIP carries an annual progression rate to MN of 0.5-1.0% as well as an increased risk of cardiovascular mortality and development of therapy-related MN in patients with solid tumors. Further studies on the natural history of ICUS, CCUS, and CHIP and to assess the risk for progression to MN are needed. Herein, we review the current understanding and clinical significance of these conditions to guide physicians in the interpretation of genetic testing results in various clinical settings.


Assuntos
Hematopoese/genética , Leucemia Mieloide/genética , Humanos
5.
Clin Lab ; 65(6)2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31232026

RESUMO

BACKGROUND: This study was designed to evaluate the effects of micro-RNA-16 (miR-16)-regulated expression of myeloblastosis oncogene (MYB) on the differentiation of acute leukemia cells, the expressions of miR-16 and MYB mRNA, and protein in differently differentiated leukemia cells were detected by real-time PCR and western blot. METHODS: 1,25-Dihydroxyvitamin D3 (1,25 D3) induced monocytic differentiation of HL60 cells, and the resulting changes in miR-16 and MYB expressions were detected. Morphology of the cells induced by 1,25 D3, after being transfection with miR-16 mimics, was observed by Wright-Giemsa staining. The expression of mononuclear cell surface marker CD14 was detected by flow cytometry. RESULTS: Minimum miR-16 was expressed in early-differentiation KG-1a cells, while late-differentiation U937 and THP-1 cells had higher expressions (p < 0.01). The expressions of MYB changed oppositely. During the monocytic differentiation of HL60 cells, miR-16 expression showed a time-dependent increase, but MYB expression gradually decreased. Overexpression of miR-16 in HL60 cells promoted 1,25 D3-induced morphological changes and CD14 expression (p < 0.05). CONCLUSIONS: MR-16 facilitated the monocytic differentiation of leukemia HL60 cells by negatively regulating MYB expression.


Assuntos
Diferenciação Celular/genética , Leucemia Mieloide/genética , MicroRNAs/genética , Proteínas Oncogênicas v-myb/genética , Doença Aguda , Calcitriol/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Células K562 , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Proteínas Oncogênicas v-myb/metabolismo , Células THP-1 , Células U937
6.
Clin Lab ; 65(6)2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31232041

RESUMO

BACKGROUND: Most cases of acute myeloid leukemia (AML) have multiple driver mutations. METHODS: We report a rare AML case with seven mutations and an aggressive clinical course. RESULTS: A 69-year-old woman presented with nausea and vomiting. A bone marrow smear showed increased mye-loblasts, promonocytes, and monocytes. Immunophenotyping identified myeloid and monocytic markers. Fusion transcripts were not detected. Massive parallel sequencing showed seven variants in DNMT3A, FLT3, KRAS, NPM1, PTPN11, and TET2. Five days after beginning chemotherapy, the patient expired. CONCLUSIONS: These findings may provide insight into the link between multiple mutations and poor prognosis.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Mieloide/genética , Mutação , Doença Aguda , Idoso , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas de Ligação a DNA/genética , Evolução Fatal , Feminino , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/tratamento farmacológico , Proteínas Nucleares/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Tirosina Quinase 3 Semelhante a fms/genética
7.
Int J Lab Hematol ; 41(5): 593-600, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31149783

RESUMO

INTRODUCTION: Acute myeloid leukemia (AML) is a heterogeneous disease associated with various genetic abnormalities. Somatic mutations in nucleophosmin 1 (NPM1), fms-related tyrosine kinase 3 (FLT3), and DNA methyltransferase 3 alpha (DNMT3A) are the most frequent mutations associated with AML. However, because DNMT3A mutations are broadly distributed, they are challenging to analyze in routine laboratory tests. Hence, we developed a rapid screening method for DNMT3A mutations by high-resolution melting (HRM) analysis for clinical use at the point of AML diagnosis. METHODS: The detection limit for DNMT3A mutations from exons 8-23 by an HRM analysis was investigated using plasmid mixtures. In 69 patients with AML, somatic mutations in NPM1, FLT3-internal tandem duplication (ITD), FLT3-tyrosine kinase domain (TKD), DNMT3A, and isocitrate dehydrogenase 1/2 were screened using HRM analysis, and direct sequencing was performed for positive samples. RESULTS: High-resolution melting analysis enabled complete mutation detection in samples with 20% mutant alleles in all regions. In a clinical laboratory test, DNMT3A mutations were detected in 12 cases (17.3%), and we identified five novel mutations. Simultaneous NPM1, FLT3-ITD, and DNMT3A mutations constituted the most common pattern (30%) in de novo cytogenetically normal AML. CONCLUSION: High-resolution melting analysis has sufficient performance for the detection of DNMT3A mutations in AML. This approach can facilitate rapid AML genotyping at diagnosis in clinical settings.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Análise Mutacional de DNA/métodos , Testes Genéticos/métodos , Leucemia Mieloide/genética , Mutação , Desnaturação de Ácido Nucleico , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mieloide/diagnóstico , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
8.
Exp Hematol ; 74: 1-12, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31154068

RESUMO

Leukemia is a complex genetic disease caused by errors in differentiation, growth, and apoptosis of hematopoietic cells in either lymphoid or myeloid lineages. Large-scale genomic characterization of thousands of leukemia patients has produced a tremendous amount of data that have enabled a better understanding of the differences between adult and pediatric patients. For instance, although phenotypically similar, pediatric and adult myeloid leukemia patients differ in their mutational profiles, typically involving either chromosomal translocations or recurrent single-base-pair mutations, respectively. To elucidate the molecular mechanisms underlying the biology of this cancer, continual efforts have been made to develop more contextually and biologically relevant experimental models. Leukemic cell lines, for example, provide an inexpensive and tractable model but often fail to recapitulate critical aspects of tumor biology. Likewise, murine leukemia models of leukemia have been highly informative but also do not entirely reproduce the human disease. More recent advances in the development of patient-derived xenografts (PDXs) or human models of leukemias are poised to provide a more comprehensive, and biologically relevant, approach to directly assess the impact of the in vivo environment on human samples. In this review, the advantages and limitations of the various current models used to functionally define the genetic requirements of leukemogenesis are discussed.


Assuntos
Diferenciação Celular , Leucemia Mieloide , Neoplasias Experimentais , Translocação Genética , Adolescente , Animais , Criança , Pré-Escolar , Feminino , Xenoenxertos , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide/genética , Leucemia Mieloide/patologia , Leucemia Mieloide/terapia , Masculino , Camundongos , Transplante de Neoplasias , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia
9.
Int J Lab Hematol ; 41(5): 607-614, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31162830

RESUMO

BACKGROUND: The MRD status detected using multiparameter flow cytometry (MFC) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) has crucial prognostic value for patients with acute myeloid leukemia (AML) in morphologic complete remission (CR). We designed a novel panel of antibodies to identify aberrant differentiation/maturation profiles of residual leukemia cells in patients who were not diagnosed at our institution, relapsed with an antigenic shift, or lack leukemia-associated immunophenotypes. METHODS: We compared the MRD status detected using MFC and real-time quantitative polymerase chain reaction (RT-qPCR) in the same 158 bone marrow samples collected from 44 AML patients carrying leukemia-specific fusion genes. The clinical performance of the MFC-based MRD status was analyzed in 168 AML patients who exhibited morphologic CR (135) or active disease (33) before HSCT. RESULTS: Strong concordance was found between MFC-based and RT-qPCR-based MRD status (κ = 0.868). Among the patients displaying CR, the positive MRD status detected using MFC was correlated with a worse prognosis [HRs (P values) for relapse, event-free survival, and overall survival: 4.83 (<0.001), 2.23 (0.003), and 1.79 (0.049), respectively]; the prognosis was similar to patients with an active disease before HSCT. Patients with a positive MRD before HSCT might experience a benefit from developing chronic graft-vs-host disease. CONCLUSIONS: The assessment of MRD using our self-built different-from-normal AML-MRD detection panel exhibited reliable sensitivity, specificity, and accuracy. In addition, patients with a positive MRD status before transplantation may have higher risk of relapse and worse survival.


Assuntos
Citometria de Fluxo/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide/terapia , Neoplasia Residual/diagnóstico , Doença Aguda , Adolescente , Adulto , Criança , Intervalo Livre de Doença , Feminino , Citometria de Fluxo/instrumentação , Humanos , Imunofenotipagem/métodos , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/genética , Proteínas de Fusão Oncogênica/genética , Prognóstico , Recidiva , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Homólogo , Adulto Jovem
10.
Methods Mol Biol ; 1974: 141-150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31099000

RESUMO

Elevated levels of microRNAs in cancer cells are often associated with oncogenic effects and thus provide potential therapeutic targets. However, the lack of efficient delivery methods for synthetic miRNA inhibitors, antagomiR, or anti-miR oligonucleotides hindered clinical translation of such strategies. We recently developed an approach for targeted delivery of synthetic, 2'-O-methyl-modified antagomiR molecules to normal and malignant myeloid cells and B cells by tethering to the single-stranded, phosphorothioate oligodeoxynucleotides (PSO). The PSO-antagomiR are rapidly internalized through scavenger receptor-mediated endocytosis by human monocytes, dendritic cells, B cells, as well as myeloid leukemia and B-cell lymphoma cells, but not by T cells. Following internalization, the unformulated PSO-antagomiR potently reduces levels of target miRNA and modulates expression of downstream protein targets, both in vitro and in vivo. The simple design of PSO-antagomiR conjugates enable adaptation of this strategy for targeting oncogenic miRNAs in nonmalignant and malignant myeloid cells and B cells.


Assuntos
Antagomirs/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Leucemia Mieloide/genética , Linfoma de Células B/genética , Animais , Linfócitos B , Humanos , Leucemia Mieloide/terapia , Linfoma de Células B/terapia , Camundongos , MicroRNAs/efeitos dos fármacos , MicroRNAs/genética , Células Mieloides/efeitos dos fármacos , Oligonucleotídeos Fosforotioatos/genética , Oligonucleotídeos Fosforotioatos/farmacologia , Linfócitos T/efeitos dos fármacos
11.
Exp Mol Pathol ; 108: 131-136, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31004601

RESUMO

KIT mutations are observed in about 20-40% of acute myeloid leukemia with t(8;21)(q22;q22.1)/RUNX1-RUNX1T1 [abbreviated AML t(8;21) here] with mutations involving exon 17 being the most common. Despite high frequencies of KIT mutations in both AML t(8;21) and systemic mastocytosis (SM), AML t(8;21) associated with SM is uncommon, and restricted to KIT exon 17 mutated cases. In this study, we report two cases of AML t(8;21) associated SM that KIT mutation occurred in exon 8 (T417_D419delinsY). In both patients, the bone marrow displayed increased round/ovoid mast cells with bilobated nuclei and absence of CD2 and CD25 expression. RUNX1/RUNX1T1 fusion was shown in both myeloblasts and mast cells by FISH. Patient #1 was refractory to induction chemotherapy and died at day 50; patient #2 had residual AML, marked SM, and persistent RUNX1/RUNX1T1 fusion after induction therapy.


Assuntos
Éxons/genética , Leucemia Mieloide/genética , Mastocitose Sistêmica/genética , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Doença Aguda , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 8 , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Evolução Fatal , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide/complicações , Leucemia Mieloide/patologia , Mastócitos/metabolismo , Mastócitos/patologia , Mastocitose Sistêmica/complicações , Mastocitose Sistêmica/diagnóstico , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Translocação Genética
12.
Genes Chromosomes Cancer ; 58(10): 698-704, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30994218

RESUMO

Deletions in the long arm of chromosome 7 (del(7q)) are recurrent cytogenetic aberrations in myeloid neoplasms. They occur either isolated or as part of a complex karyotype and are associated with unfavorable prognosis in certain disease entities. We performed detailed cytogenetic analysis, molecular analysis, and array comparative genomic hybridization in a cohort of 81 patients with a variety of myeloid malignancies and del(7q) as sole chromosomal alteration. In 70% (57/81) of patients, we identified a commonly deleted region (size: 18 Mb) involving the genomic region 101 912.442 (7q22.1)-119 608.824 (7q31.31). Furthermore, in 80 patients, we analyzed 17 genes commonly mutated in myeloid neoplasms and identified high mutation frequencies in ASXL1 34% (27/80), TET2 33% (26/80), RUNX1 25% (20/80), DNMT3A 25% (20/80), while TP53 was rarely affected (5%, 4/80). ASXL1 and TET2 showed similar mutation frequencies across all analyzed entities while RUNX1, CBL, and JAK2 were specifically mutated in patients with acute myeloid leukemia (AML), chronic myelomonocytic leukemia, and myeloproliferative neoplasms, respectively. We detected a significantly higher frequency of RUNX1 (42% vs 13%, P = .0001) and ASXL1 (32% vs 14%, P = .008) mutations in AML patients with del(7q) compared to other AML patients in the Medical Research Council unfavorable risk group (n = 464), indicating a cooperative leukemogenic potential. Our data provide further insight into the pathomechanism of this cytogenetic subgroup.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Leucemia Mieloide/genética , Taxa de Mutação , Subunidade alfa 2 de Fator de Ligação ao Core/genética , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas de Ligação a DNA/genética , Humanos , Janus Quinase 2/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-cbl/genética , Proteínas Repressoras/genética , Proteína Supressora de Tumor p53/genética
13.
Oncogene ; 38(27): 5530-5540, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30967629

RESUMO

Hyperproliferative cancer cells face increased replication stress, which can result in accumulation of DNA damage. As DNA damage can arrest proliferation, and, in the case of myeloid leukemia, induce differentiation of cancer cells, understanding the mechanisms that regulate the replication stress response is paramount. Here, we show that PARI, a replisome protein involved in regulating DNA repair and replication stress, suppresses differentiation of myeloid leukemia cells. We show that PARI is overexpressed in myeloid leukemia cells, and its knockdown reduces leukemia cell proliferation in vitro and in vivo in xenograft mouse models. PARI depletion enhances replication stress and DNA-damage accumulation, coupled with increased myeloid differentiation. Mechanistically, we show that PARI inhibits activation of the NF-κB pathway, which can initiate p21-mediated differentiation and proliferation arrest. Finally, we show that PARI expression negatively correlates with expression of differentiation markers in clinical myeloid leukemia samples, suggesting that targeting PARI may restore differentiation ability of leukemia cells and antagonize their proliferation.


Assuntos
Diferenciação Celular/fisiologia , Proteínas de Ligação a DNA/fisiologia , Leucemia Mieloide/patologia , Proliferação de Células/fisiologia , Dano ao DNA , Proteínas de Ligação a DNA/genética , Técnicas de Silenciamento de Genes , Células HL-60 , Humanos , Leucemia Mieloide/genética , NF-kappa B/metabolismo , Ligação Proteica , Células U937
15.
Mol Med Rep ; 19(4): 3247-3254, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816462

RESUMO

Previous studies have demonstrated that ENDOCAN is elevated in leukemia, and it has been reported to be associated with poor prognosis. However, the functional role of ENDOCAN in the development of leukemia remains to be fully elucidated. In the present study, the expression levels of ENDOCAN were detected in THP­1, U937, HL­60 and K562 cells, and it was found that ENDOCAN was increased in U937 and K562 cells, compared with the other two cell lines. Subsequently, ENDOCAN was knocked down in U937 and K562 cells via lentiviral infection. It was found that cell proliferation and the expression of proliferating cell nuclear antigen were inhibited in myeloid leukemia cells following the silencing of ENDOCAN. ENDOCAN knockdown induced G0/G1­phase cell cycle arrest in myeloid leukemia cells with a decreased expression of cyclin D1. Furthermore, cell apoptosis was increased in response to ENDOCAN silencing, which was accompanied by the downregulation of B­cell lymphoma (BCL2) and the upregulation of BCL2­associated X protein, cleaved caspases 3 and 9, and cleaved poly (ADP­ribose) polymerase. Furthermore, it was demonstrated that the knockdown of ENDOCAN inhibited nuclear factor­κB (NF­κB) activity, as evidenced by the increased expression of NF­κB inhibitor α (IκBα), decreased expression of phosphorylated (p­)IκBα, p­P65 and nuclear P65, and reduced NF­κB DNA­binding activity. In combination, the present findings suggested that ENDOCAN may serve as a potential therapeutic target in the treatment of leukemia.


Assuntos
Apoptose/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , NF-kappa B/metabolismo , Proteínas de Neoplasias/genética , Proteoglicanas/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Inativação Gênica , Células HL-60 , Humanos , Células K562 , Leucemia Mieloide/patologia , Células U937
16.
Braz J Med Biol Res ; 52(2): e8194, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30785480

RESUMO

Cytogenetics is essential in myeloid neoplasms (MN) and pre-analytical variables are important for karyotyping. We assessed the relationship between pre-analytical variables (time from collection to sample processing, material type, sample cellularity, and diagnosis) and failures of karyotyping. Bone marrow (BM, n=352) and peripheral blood (PB, n=69) samples were analyzed from acute myeloid leukemia (n=113), myelodysplastic syndromes (n=73), myelodysplastic syndromes/myeloproliferative neoplasms (n=17), myeloproliferative neoplasms (n=137), and other with conclusive diagnosis (n=6), and reactive disorders/no conclusive diagnosis (n=75). The rate of unsuccessful karyotyping was 18.5% and was associated with the use of PB and a low number of nucleated cells (≤7×103/µL) in the sample. High and low cellularity in BM and high and low cellularity in PB samples showed no metaphases in 3.9, 39.7, 41.9, and 84.6% of cases, respectively. Collecting a good BM sample is the key for the success of karyotyping in MN and avoids the use of expensive molecular techniques.


Assuntos
Células da Medula Óssea/patologia , Cariotipagem/métodos , Leucemia Mieloide/genética , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Manejo de Espécimes/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mieloide/diagnóstico , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Transtornos Mieloproliferativos/diagnóstico , Manejo de Espécimes/normas , Adulto Jovem
17.
Mol Ther ; 27(3): 542-558, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30799283

RESUMO

Erbin has been shown to have significant effects on the development of solid tumors. However, little is known about its function and regulatory mechanism in hematological malignancies. The biological function of Erbin on cell proliferation was measured in vitro and in vivo. The predicted target of Erbin was validated by dual-luciferase reporter assay and rescue experiment. We found that overexpression of Erbin could inhibit the cell proliferation and promote the cell differentiation of acute myeloid leukemia (AML) cells, whereas depletion of Erbin could enhance the cell proliferation and block the cell differentiation in AML cells in vitro and in vivo. Besides, miR-183-5p was identified as the upstream regulator that negatively regulated the Erbin expression. The results were confirmed by dual-luciferase reporter and RNA pull-down assay. Furthermore, we found that miR-183-5p negatively regulated Erbin, resulting in enhanced cell proliferation of AML cells via activation of RAS/RAF/MEK/ERK and PI3K/AKT/FoxO3a pathways. The activation of RAS/RAF/MEK/ERK and PI3K/AKT/FoxO3a pathways was mediated by Erbin interacting with Grb2. These results were also validated by rescue experiments in vitro and in vivo. All above-mentioned findings indicated that the miR-183-5p/Erbin signaling pathway might represent a novel prognostic biomarker or therapeutic target for treatment of AML.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Diferenciação Celular/fisiologia , Proteína Forkhead Box O3/metabolismo , Leucemia Mieloide/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Proliferação de Células/fisiologia , Citometria de Fluxo , Proteína Forkhead Box O3/genética , Células HL-60 , Humanos , Leucemia Mieloide/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Células U937
18.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(2): 112-115, 2019 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-30703225

RESUMO

OBJECTIVE: To explore the clinical and laboratory characteristics of 5 patients with myeloid leukemia and t(12;22)(p13;q12). METHODS: Bone marrow cells were cultured for 24 h and analyzed by standard R-banding. Rearrangement of the MN1 gene was detected by fluorescence in situ hybridization (FISH) using dual color break-apart MN1 probes. MN1-ETV6 and ETV6-MN1 fusion genes were detected by reverse transcription polymerase chain reaction (RT-PCR). And the products were subjected to direct sequencing. RESULTS: Among the 5 patients, 2 had AML-M0, 2 had AML-M4, and 1 had CMM0L at the initial diagnosis. t(12;22)(p13;q12) was the primary abnormality among all patients. Rearrangements of MN1 gene were detected by FISH in all patients. MN1-ETV6 and ETV6-MN1 fusion genes were detected respectively in 4 and 3 patients. CONCLUSION: t(12;22)(p13;q12) is a rare but recurrent chromosomal abnormality in myeloid leukemia, and is related to poor prognosis. allo-SCT is valuable for patients with t(12;22)(p13;q12).


Assuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 22 , Leucemia Mieloide , Translocação Genética , Bandeamento Cromossômico , Citogenética , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide/genética , Proteínas de Fusão Oncogênica
19.
Biochim Biophys Acta Mol Cell Res ; 1866(1): 144-152, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30026077

RESUMO

Cancer cells depend on a supportive niche (the tumor microenvironment) that promotes tumor cell survival while protecting the malignant cells from therapeutic challenges and the host's defense systems. Cancer cells and the support cells in the tumor microenvironment communicate via cytokines/chemokines, cell:cell contact, or alterations in the metabolic state of the niche (e.g. hypoxia) that promote growth and survival of the tumor cell, influence metastasis, and defeat immune surveillance. These signaling pathways involve dysregulation of not only protein kinases but also protein phosphatases as normal signal transduction processes require both activation and deactivation. For instance, aberrant receptor signaling can result from constitutive activation of a tyrosine kinase such as FLT3 or inactivation of a tyrosine protein phosphatase such as SHP-2 (PTPN11). Activation of serine/threonine kinases such as AKT and ERK are often observed during the development of drug resistance while genomic and non-genomic suppression of serine/threonine protein phosphatases such as PP2A achieve similar results. It is fairly clear that the various protein phosphatases will impact processes that support drug resistance. Of growing interest is the emerging model whereby the support cells in the tumor microenvironment actually serve as drivers of tumorigenesis. This phenomenon has been most prominently observed in osteoblast cells in leukemic niches. At least one protein phosphatase, PTPN11, has emerged as a critical driver of this process in juvenile myelomonocytic leukemia. This review will cover the role of various serine/threonine and tyrosine protein phosphatases in processes that are central to tumor microenvironment function.


Assuntos
Fosfoproteínas Fosfatases/metabolismo , Fosfoproteínas Fosfatases/fisiologia , Microambiente Tumoral/fisiologia , Diferenciação Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Mieloide/genética , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Fosforilação , Proteína Fosfatase 1/metabolismo , Proteína Fosfatase 2/metabolismo , Proteína Fosfatase 2/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/fisiologia , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais
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