Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 8.903
Filtrar
1.
Expert Opin Investig Drugs ; 28(10): 835-849, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31510809

RESUMO

Introduction: The incidence of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) is increasing with the aging population. Prognosis and overall survival (OS) remain poor in elderly patients and in those not eligible for intensive treatment. Hypomethylating agents (HMAs) have played an important role in this group of patients but their efficacy is limited. Areas covered: This article reviews the mechanism of action, pharmacology, safety profile and clinical efficacy of subcutaneous guadecitabine, a second-generation DNA methylation inhibitor in development for the treatment of AML and MDS. Expert opinion: Although guadecitabine did not yield improved complete remission (CR) rates and OS compared to the control arm in patients with treatment-naïve AML who were ineligible for intensive chemotherapy, subgroup analysis in patients who received ≥4 cycles of therapy demonstrated superior outcomes in favor of guadecitabine. Given its stability, ease of administration, safety profile and prolonged exposure time, guadecitabine would be the more appropriate HMA, replacing azacitidine and decitabine, to be used combination treatment regimens in patients with myeloid malignancies.


Assuntos
Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/farmacologia , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Humanos , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/patologia , Prognóstico , Taxa de Sobrevida , Fatores de Tempo
2.
Chem Biol Interact ; 311: 108793, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31421117

RESUMO

Polyphyllin I (PPI), a bioactive component extracted from Paris polyphylla, was reported to have potent anticancer activities in previous studies. However, there were few reports on the effects and underlying mechanism of PPI in human acute myeloid leukemia cells. The present study demonstrated that PPI had an inhibitory effect through inducing apoptosis and autophagy in THP-1 and NB4 cells. PPI induced apoptosis via activating JNK pathway, as evidenced by the decreased Bcl-2 levels and increased Bax, cleaved-caspase-3 and phosphorylated-JNK expressions. In addition, PPI promoted autophagy as evidenced with increased expressions of LC3-II and Beclin-1 in western blot and autophagic vacuoles in MDC staining, which was associated with the inhibition of AKT-mTOR pathway. Furthermore, JNK inhibitor SP600125 and autophagy inhibitor 3-MA were employed to evaluate the role of apoptosis and autophagy in PPI-induced cell death. We found that autophagy and apoptosis were both causes of cell death induced by PPI. These data suggested that PPI could be a potent therapeutic agent for the treatment of human acute myeloid leukemia.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Diosgenina/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Diosgenina/farmacologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima/efeitos dos fármacos
3.
Bioengineered ; 10(1): 345-352, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31411110

RESUMO

This study aimed to detect serum miR-203 expression levels in AML and explore its potential clinical significance. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to measure the serum miR-203 levels in 134 patients with AML and 70 healthy controls. The results demonstrated that serum miR-203 expression was significantly reduced in AML patients compared with healthy controls. Receiver operating characteristic curve (ROC) analysis revealed miR-203 could distinguish AML cases from normal controls. Low serum miR-203 levels were associated with worse clinical features, as well as poorer overall survival and relapse free survival of AML patients. Moreover, multivariate analysis confirmed low serum miR-203 expression to be an independent unfavorable prognostic predictor for AML. The bioinformatics analysis showed that the downstream genes and pathways of miR-203 was closely associated with tumorigenesis. Downregulation of miR-203 in AML cell lines upregulated the expression levels of oncogenic promoters such as CREB1, SRC and HDAC1. Thus, these findings demonstrated that serum miR-203 might be a promising biomarker for the diagnosis and prognosis of AML.


Assuntos
Biomarcadores Tumorais/genética , Carcinogênese/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , MicroRNAs/genética , Proteínas de Neoplasias/genética , Antagomirs/genética , Antagomirs/metabolismo , Biomarcadores Tumorais/sangue , Carcinogênese/metabolismo , Carcinogênese/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Biologia Computacional/métodos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/sangue , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Perfilação da Expressão Gênica , Ontologia Genética , Histona Desacetilase 1/sangue , Histona Desacetilase 1/genética , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , MicroRNAs/antagonistas & inibidores , MicroRNAs/sangue , Anotação de Sequência Molecular , Análise Multivariada , Proteínas de Neoplasias/sangue , Prognóstico , Curva ROC , Recidiva , Transdução de Sinais , Análise de Sobrevida , Quinases da Família src/sangue , Quinases da Família src/genética
5.
Life Sci ; 232: 116663, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31323275

RESUMO

AIMS: CD123 represents an important acute myeloid leukemia (AML) therapeutic target. CD123 aptamers may potentially serve as tumor-homing ligands with excellent affinity and specificity for AML targeted therapy, but their complexity, laborious preparation and nuclease digestion limited pharmacological application. The aim of this study was to develop the first CD123 thioaptamer to overcome these obstacles. MAIN METHODS: Flow cytometry was utilized to assess the binding specificity, affinity and anti-nuclease ability of thioaptamer. CCK8, Annexin-V/DAPI, and colony forming assays were used to evaluate the anti-cancer ability of thioaptamer in vitro. The tumor volume, weights, survival rate, H&E staining of organs, and serum level of organ damage biomarkers of animal model were applied to investigate the anti-cancer ability of thioaptamer in vivo. Furthermore, we explored the binding mechanism between thioaptamer and CD123. KEY FINDINGS: CD123 thioaptamer SS30 was able to bind to CD123 structure with high specificity in complex nuclease environment, the dissociation constant of 39.1 nM for CD123 peptide and 287.6 nM for CD123+ AML cells, while exhibiting minimal cross-reactivity to albumin. Furthermore, SS30 inhibited the proliferation and survival of AML cell lines and human AML blasts selectively in vitro (P < 0.01). In addition, SS30 prolonged the survival and inhibited tumor growth in a mouse xenograft tumor model in vivo. Of note, SS30 blocked the interaction between IL-3 and CD123, and decreased expression of p-STAT5 and p-AKT. SIGNIFICANCE: The proliferation inhibition and nuclease resistance ability of SS30 made it as a more promising functional molecule for AML targeted therapy.


Assuntos
Antineoplásicos/farmacologia , Aptâmeros de Peptídeos/farmacologia , Proliferação de Células/efeitos dos fármacos , Subunidade alfa de Receptor de Interleucina-3/efeitos dos fármacos , Leucemia Mieloide Aguda/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Interleucina-3/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos
6.
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
8.
Eur J Med Chem ; 178: 468-483, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31207462

RESUMO

Acute myeloid leukemia (AML) is a malignant disease characterized by abnormal growth and differentiation of hematopoietic stem cells. Although the pathogenesis has not been fully elucidated, many specific gene mutations have been found in AML. Fms-like tyrosine kinase 3 (FLT3) is recognized as a drug target for the treatment of AML, and the activation mutations of FLT3 were found in about 30% of AML patients. Targeted inhibition of FLT3 receptor tyrosine kinase has shown promising results in the treatment of FLT3 mutation AML. Unfortunately, the therapeutic effects of FLT3 tyrosine kinase inhibitors used as AML monotherapy are usually accompanied by the high risk of resistance development within a few months after treatment. FLT3 dual inhibitors were generated with the co-inhibition of FLT3 and another target, such as CDK4, JAK2, MEK, Mer, Pim, etc., to solve the problems mentioned above. As a result, the therapeutic effect of the drug is significantly improved, while the toxic and side effects are reduced. Besides, the life quality of AML patients with FLT3 mutation has been effectively improved. In this paper, we reviewed the studies of dual FLT3 inhibitors that have been discovered in recent years for the treatment of AML.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tirosina Quinase 3 Semelhante a fms/metabolismo
9.
Biochim Biophys Acta Rev Cancer ; 1872(1): 80-88, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31201827

RESUMO

FLT3 overexpression is a recurrent event in various acute leukaemia subtypes. This transcriptional deregulation is important to define the prognostic risk for many patients. Of note, the molecular mechanisms leading to this gene upregulation are unknown for a substantial number of cases. In this Mini-Review, we highlight the role of FLT3 overexpression in acute leukaemia and discuss emerging mechanisms accounting for this upregulation. The benefits of using targeted therapy are also addressed in the overexpression context, posing other therapeutic possibilities based on state-of-the-art knowledge that could be considered for future research.


Assuntos
Leucemia Mieloide Aguda/genética , Tirosina Quinase 3 Semelhante a fms/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Leucemia Mieloide Aguda/patologia , Mutação , Prognóstico
11.
Adv Clin Exp Med ; 28(7): 861-869, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31199877

RESUMO

BACKGROUND: Cytostatic treatment induces apoptosis or other types of cell death like autophagy, necrosis, mitotic catastrophe, etc. Autophagy can play a role in the drug resistance of neoplastic cells, allowing the survival of blast cells under stressful conditions, such as the use of cytostatics. Studies on apoptosis and autophagy 12-24 h after the start of treatment have not been conducted until now. OBJECTIVES: The study aimed to investigate the predictive and prognostic significance of autophagy and apoptosis in patients with acute myeloid leukemia (AML). MATERIAL AND METHODS: The study included 38 patients. Blood was collected before and 12-24 h after the start of treatment, since at that time point, the appropriate blast cell count was still available. Autophagy was measured with the expression of the ATG5, MAP1L3, LC3-I, and LC3-II proteins. The percentage of mononuclear cells in early and late apoptosis was evaluated with flow cytometry, using the annexin V and propidium iodide (PI) binding assay. RESULTS: The percentage of apoptotic blast cells before treatment was not associated with the response. However, in the remission group, the overall percentage of apoptotic cells measured 12-24 h after the start of treatment was higher than in non-remission patients, which was statistically significant. In neither group we found any difference in the level of autophagy before and 12-24 h after the start of treatment. Nevertheless, we observed an increasing tendency of the MAP1LC3 protein expression (not statistically significant) in the remission group 12-24 h after the start of treatment. Patients with a higher percentage of blast cells in apoptosis and with a higher expression of MAP1LC3 protein measured 12-24 h after the start of the therapy had longer overall survival (OS). CONCLUSIONS: A higher percentage of apoptotic as well as autophagic blast cells measured 12-24 h after the start of the chemotherapy is an independent factor associated with better outcomes.


Assuntos
Apoptose , Autofagia , Crise Blástica , Leucemia Mieloide Aguda , Proteínas Associadas aos Microtúbulos/metabolismo , Antineoplásicos/uso terapêutico , Citometria de Fluxo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Prognóstico , Taxa de Sobrevida
12.
Nat Commun ; 10(1): 2723, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31222014

RESUMO

Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Transativadores/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Medula Óssea/patologia , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Epigênese Genética/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de RNA , Análise de Célula Única , Transativadores/genética , Transativadores/metabolismo , Transcrição Genética/efeitos dos fármacos , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Ann Hematol ; 98(8): 1927-1932, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31187237

RESUMO

Patients with acute myeloid leukemia (AML) who progress after exposure to hypomethylating agents (HMA) have a dismal prognosis. We hypothesized that the addition of venetoclax, a BCL-2 inhibitor, to AML patients who previously failed HMA might overcome resistance. Adult patients (≥ 18 years) with AML were eligible if leukemia relapsed after, or was refractory to HMA. In general, in addition to venetoclax, patients continued HMA or other low-intensity therapies. Patients who previously underwent allogeneic hematopoietic cell transplantation (HCT) were also eligible. Data were analyzed in November 2018. Twenty-three patients were treated between October 2016 and October 2018 and were eligible for this study. Median age was 76 years and 6 patients had leukemia that relapsed post allogeneic HCT. None of the patients experienced tumor lysis syndrome and toxicities were as expected and manageable. Febrile neutropenia was the most common toxicity (78% of patients). Median hospitalization time was 13 days. Forty-three percent of the patients achieved CR/CRi. Overall survival (OS) was 74% at 6 months and median OS in patients who achieved remission was 10.8 months. Higher number of blasts in both bone marrow and peripheral blood was associated with lower chances of CR, while higher WBC, LDH, and bone marrow or peripheral blasts were associated with increased mortality rate. The addition of venetoclax to patients with HMA-refractory AML may result in a substantial anti-leukemic activity, specifically in those achieving complete remission. This should be further tested in a well-designed prospective trial.


Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Neutropenia Febril Induzida por Quimioterapia/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Azacitidina/administração & dosagem , Neutropenia Febril Induzida por Quimioterapia/etiologia , Neutropenia Febril Induzida por Quimioterapia/mortalidade , Decitabina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Análise de Sobrevida , Transplante Homólogo
14.
Eur J Med Chem ; 175: 357-372, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31096156

RESUMO

Lysine-specific demethylase 1 (LSD1), demethylase against mono- and di - methylated histone3 lysine 4, has emerged as a promising target in oncology. More specifically, it has been demonstrated as a key promoter in acute myeloid leukemia (AML), and several LSD1 inhibitors have already entered into clinical trials for the treatment of AML. In this paper, a series of new indole derivatives were designed and synthesized based on a lead compound obtained by a high-throughput screening with our in-house compound library. Among the synthetic compounds, 9e was characterized as a potent LSD1 inhibitor with an IC50 of 1.230 µM and can inhibit the proliferation of THP-1 cells effectively. And most importantly, this is the first irreversible LSD1 inhibitor that is not derived from monoamine oxidase inhibitors. Hence, the discovery of 9e may serve as a proof of concept work for AML treatment.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Indóis/síntese química , Indóis/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Furanos/química , Ensaios de Triagem em Larga Escala , Histona Desmetilases/metabolismo , Humanos , Indóis/química , Indóis/metabolismo , Concentração Inibidora 50 , Leucemia Mieloide Aguda/patologia , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
15.
J Pediatr Endocrinol Metab ; 32(5): 537-541, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31075084

RESUMO

Hematopoietic stem cell transplantation (HSCT) has been newly identified as an etiology underlying acquired lipodystrophy (ALD). We report about two children with leukemia who underwent HSCT and later manifested aberrant fat distributions consistent with acquired partial lipodystrophy (APL). Both patients manifested graft-versus-host disease (GVHD), suggesting that GVHD may trigger lipodystrophy. The patients exhibited diabetic blood glucose patterns in the oral glucose tolerance test (OGTT) with high homeostasis model assessment ratios (HOMA-Rs), hypertriglyceridemia, fatty liver, and decreased serum leptin and adiponectin levels. Both patients were diagnosed with APL with metabolic disease. A review of the data of patients with ALD after HSCT revealed common clinical features, including aberrant fat distribution, impaired glucose tolerance (IGT) or diabetes and dyslipidemia. Based on previous reports and our two cases, we speculate that GVHD in the adipose tissue supports the development of ALD after HSCT. In conclusion, children may develop APL after HSCT. Therefore, evaluations of fat distribution and metabolic disease may be important during the long-term follow-up of these patients.


Assuntos
Fígado Gorduroso/etiologia , Intolerância à Glucose/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hipertrigliceridemia/etiologia , Leucemia Mieloide Aguda/terapia , Lipodistrofia/etiologia , Doenças Metabólicas/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Criança , Fígado Gorduroso/patologia , Feminino , Intolerância à Glucose/patologia , Humanos , Hipertrigliceridemia/patologia , Lactente , Leucemia Mieloide Aguda/patologia , Lipodistrofia/patologia , Doenças Metabólicas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico
16.
Adv Exp Med Biol ; 1139: 153-169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31134500

RESUMO

The failure of complete remissions to reliably translate into cures in acute myeloid leukemia (AML) can be explained by the leukemia stem cell (LSC) paradigm, which hypothesizes that rare leukemia cells with stem cell features, including self-renewal capacity and drug resistance, are primarily responsible for both disease maintenance and relapses. Traditionally, the ability to generate AML in immunocompromised mice were how these so-called LSCs were identified. Only those rare AML cells characterized by a hematopoietic stem cell (HSC) CD34+CD38- phenotype were believed capable of generating leukemia in immunocompromised mice, but more recently, significant heterogeneity in the phenotypes of engrafting AML cells has been demonstrated. Moreover, AML cells that engraft immunocompromised mice do not necessarily represent either the founder clone or those cells responsible for relapse. A recent study found that the most immature phenotype present in an AML was heterogeneous, but correlated with genetically defined risk groups and outcomes. Patients with AML cells expressing a primitive HSC phenotype (CD34+CD38- with high aldehyde dehydrogenase activity) manifested significantly lower complete remission rates, as well as poorer event-free and overall survivals. AMLs in which the most primitive cells displayed more mature phenotypes were associated with better outcomes. The strong clinical correlations suggest that the most immature phenotype detectable within a patient's AML might serve as a biomarker for "clinically relevant" LSCs. The minimal residual disease state during first remission may be the optimal setting to study novel LSC-targeted therapies, since they may have limited activity against the bulk leukemia and will be utilized at lowest tumor burden as well as least tumor heterogeneity.


Assuntos
Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/citologia , Animais , Antígenos CD34 , Biomarcadores , Células-Tronco Hematopoéticas , Humanos , Camundongos , Fenótipo
17.
Indian J Cancer ; 56(2): 167-172, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31062738

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) patients with non-remission (NR) after the first cycle of standard induction chemotherapy remain a challenge owing to poor response and tolerance to re-induction regimen. We retrospectively evaluated the efficacy and safety of three regimens in AML patients refractory to the first course of standard induction regimen. MATERIALS AND METHODS: The three regimens consisted of (1) High-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor (HD-CAG) regimen (n = 44); (2) intermediate/high-dose cytarabine (I/HDAC) regimen (n = 30); and (3) standard-dose cytarabine (SDAC) combination regimen that was identical to the first course of standard induction regimen (n = 27). RESULTS: Results indicated that after the second course, the overall response (OR), i.e., complete remission [CR]+partial remission [PR]) rates in HD-CAG was higher than in the I/HDAC group (84.1% vs. 56.7%, P = 0.009), whereas the CR rates among 3 groups were not statistically different (P = 0.541). Meanwhile, the proportion of subjects reporting certain adverse effects in the HD-CAG group was lower than the I/HDAC or SDAC groups. There were no significant differences in overall survival (OS) and disease-free survival (DFS) rates among the 3 groups (P = 0.881 and P = 0.872, respectively). CONCLUSION: Our preliminary results indicate that HD-CAG regimen may represent a better alternative option for AML patients with NR after the first course of standard induction chemotherapy.


Assuntos
Aclarubicina/administração & dosagem , Citarabina/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos
18.
Int J Clin Oncol ; 24(8): 893-898, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31111287

RESUMO

The development of allogeneic hematopoietic-stem-cell transplantation has improved the prognosis of younger acute myeloid leukemia (AML) patients. However, the outcome of older AML patients remains poor. The majority of AML patients are elderly. For elderly AML patients unfit for intensive chemotherapy, less toxic single agent that targets a specific gene mutation or combination therapy with a single agent is needed. The role of chromosomal abnormalities and genetic mutations in leukemia has become more apparent, and detailed prognostic stratification based on the type of genetic mutation has been established. Next-generation sequencing (NGS) has been used for gene analysis of AML. In the future, the evaluation of biologically homogeneous population on the basis of chromosomal abnormalities and gene mutations will lead to a paradigm shift that will help in the development of optimized therapy. As rapid diagnosis of gene mutations is required by the clinical physicians to decide on induction therapy, it is important to have a swift turnaround time for comprehensive DNA sequencing to provide actionable data to clinical physicians. It is required to conduct a feasibility study to evaluate the turnaround time from sending the specimens to receiving the results while maintaining the quality of the specimens contributing to gene analysis. To detect infrequent gene mutations, investigators need to perform multicenter studies and/or cooperative-group trials with a certain sample size to examine the frequency of the gene mutations in elderly AML patients, enabling sufficient statistical power for meaningful comparisons.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Medicina de Precisão , Neoplasias Hematológicas/genética , Humanos , Japão , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mutação , Prognóstico
19.
Nat Commun ; 10(1): 2031, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31048683

RESUMO

Mutations in the nucleophosmin 1 (NPM1) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To characterize the genetic composition of NPM1 mutated (NPM1mut) AML, we assess mutation status of five recurrently mutated oncogenes in 129 paired NPM1mut samples obtained at diagnosis and relapse. We find a substantial shift in the genetic pattern from diagnosis to relapse including NPM1mut loss (n = 11). To better understand these NPM1mut loss cases, we perform whole exome sequencing (WES) and RNA-Seq. At the time of relapse, NPM1mut loss patients (pts) feature distinct mutational patterns that share almost no somatic mutation with the corresponding diagnosis sample and impact different signaling pathways. In contrast, profiles of pts with persistent NPM1mut are reflected by a high overlap of mutations between diagnosis and relapse. Our findings confirm that relapse often originates from persistent leukemic clones, though NPM1mut loss cases suggest a second "de novo" or treatment-associated AML (tAML) as alternative cause of relapse.


Assuntos
Evolução Clonal , Leucemia Mieloide Aguda/genética , Recidiva Local de Neoplasia/genética , Segunda Neoplasia Primária/genética , Proteínas Nucleares/genética , Adulto , Idoso , Análise Mutacional de DNA , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/patologia , Segunda Neoplasia Primária/patologia , Sequenciamento Completo do Exoma
20.
Artif Cells Nanomed Biotechnol ; 47(1): 1730-1737, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31062614

RESUMO

LncRNA SBF2-AS1 has been reported to be implicated in the deterioration of multiple human cancers. However, the roles and underlying mechanisms of SBF2-AS1 in acute myeloid leukemia (AML) are still unclear. In the present study, the online GEPIA database showed that SBF2-AS1 expression was significantly increased in AML samples. QRT-PCR results showed that SBF2-AS1 expression was upregulated in AML cells. CCK-8 assay revealed that SBF2-AS1 inhibition decreased AML cells proliferation ability in vitro. Flow cytometry assays showed that SBF2-AS1 inhibition induced AML cells apoptosis and arrested AML cells in G0/G1 phase. Mechanistically, miR-188-5p was identified as a direct target of SBF2-AS1. SBF2-AS1 upregulated the expression level of ZFP91 by sponging miR-188-5p. And the effects of SBF2-AS1 suppression on AML cells progression could be abolished by miR-188-5p inhibitors. Moreover, we found that SBF2-AS1 inhibition reduced tumor growth in vivo. Taken together, our findings elucidated that SBF2-AS1 could act as a miRNA sponge in AML progression, and provided a potential therapeutic strategy for AML treatment.


Assuntos
Leucemia Mieloide Aguda/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Animais , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Camundongos , Ubiquitina-Proteína Ligases/genética , Regulação para Cima/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA