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1.
Orv Hetil ; 161(38): 1623-1628, 2020 09.
Artigo em Húngaro | MEDLINE | ID: mdl-32924966

RESUMO

Maintenance therapy has been the strong and standard element of many acute lymphoblastic leukaemia protocols, used much less frequently and systematically in adult oncohematological disorders. The first adult maintenance efforts appeared in follicular and mantle cell lymphoma (mostly monoclonal antibody based), along with an early maintenance effort to prolong the plateau phase of myeloma. For the time being, after a long debate, the prognosis-dependent type of consolidation and maintenance became - sometimes until relapse - the standard approach in myeloma patients. The so-called small molecules, which turned out to be effective as induction and relapse agents, are continuously moving toward maintenance settings. Moreover, maintenance efforts seem to be more and more considered and used in transplanted or some non-transplanted acute myeloid leukaemia patients as well. Nevertheless, maintenance should be patient-friendly, easy to use (e.g., tablets) by enabling short outpatient office time, done not very frequently, and as much quality-of-life-based as possible. Orv Hetil. 2020; 161(38): 1623-1628.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto , Humanos , Leucemia Mieloide Aguda/patologia , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
2.
Tumour Biol ; 42(9): 1010428320954735, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32873193

RESUMO

Acute myeloid leukemia is the most common form of acute leukemia in adults, constituting about 80% of cases. Although remarkable progress has been made in the therapeutic scenario for patients with acute myeloid leukemia, research and development of new and effective anticancer agents to improve patient outcome and minimize toxicity is needed. In this study, the antitumor activity of axolotl (AXO) Ambystoma mexicanum crude extract was assessed in vitro on the human acute myeloid leukemia HL-60 cell line. The anticancer activity was evaluated in terms of ability to influence proliferative activity, cell viability, cell cycle arrest, and differentiation. Moreover, gene expression analysis was performed to evaluate the genes involved in the regulation of these processes. The AXO crude extract exhibited antiproliferative but not cytotoxic activities on HL-60 cells, with cell cycle arrest in the G0/G1 phase. Furthermore, the AXO-treated HL-60 cells showed an increase in both the percentage of nitroblue tetrazolium positive cells and the expression of CD11b, whereas the proportion of CD14-positive cells did not change, suggesting that extract is able to induce differentiation toward the granulocytic lineage. Finally, the treatment with AXO extract caused upregulation of CEBPA, CEBPB, CEBPE, SPI1, CDKN1A, and CDKN2C, and downregulation of c-MYC. Our data clearly show the potential anticancer activity of Ambystoma mexicanum on HL-60 cells and suggest that it could help develop promising therapeutic agents for the treatment of acute myeloid leukemia.


Assuntos
Ambystoma mexicanum , Proliferação de Células/efeitos dos fármacos , Misturas Complexas/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p18/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Proteínas Proto-Oncogênicas c-myc/genética
4.
PLoS One ; 15(8): e0235503, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760083

RESUMO

PURPOSE: We evaluated the outcomes of decitabine as first-line treatment in older patients with acute myeloid leukemia (AML) and investigated the predictors, including a baseline mini nutritional assessment short form (MNA-SF) score, of response and survival. PATIENTS AND METHODS: Between 2010 and 2018, 96 AML patients aged 65 and above who received decitabine treatment at 6 centers in Korea were retrospectively evaluated. Response rates, hematologic improvements (HI), progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: The median age at diagnosis was 73.9 years, and the median number of decitabine treatments administered to the patients was 4 (range, 1-29). Of 85 patients, 15 patients (17.6%) achieved complete remission (CR) or CR with incomplete blood count recovery. Twelve patients (14.1%) showed partial remission (PR), and 18 (21.2%) demonstrated HI without an objective response. The median PFS and OS were 7.0 (95% confidence interval [CI], 4.9-9.0) and 10.6 (95% CI, 7.7-13.5%) months, respectively. In multivariate analyses, MNA-SF score ≥ 8 and the absence of peripheral blood (PB) blasts were significant predictors for improved PFS and OS. CONCLUSIONS: For older patients with newly diagnosed AML, a high MNA-SF score and the absence of PB blasts were independently associated with improved survival.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Decitabina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Indução de Remissão/métodos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Contagem de Células Sanguíneas , Medula Óssea/patologia , Decitabina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Avaliação Nutricional , Intervalo Livre de Progressão , República da Coreia/epidemiologia , Estudos Retrospectivos , Perda de Peso
5.
Nat Commun ; 11(1): 4056, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792483

RESUMO

Autophagy has been associated with oncogenesis with one of its emerging key functions being its contribution to the metabolism of tumors. Therefore, deciphering the mechanisms of how autophagy supports tumor cell metabolism is essential. Here, we demonstrate that the inhibition of autophagy induces an accumulation of lipid droplets (LD) due to a decrease in fatty acid ß-oxidation, that leads to a reduction of oxidative phosphorylation (OxPHOS) in acute myeloid leukemia (AML), but not in normal cells. Thus, the autophagic process participates in lipid catabolism that supports OxPHOS in AML cells. Interestingly, the inhibition of OxPHOS leads to LD accumulation with the concomitant inhibition of autophagy. Mechanistically, we show that the disruption of mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) phenocopies OxPHOS inhibition. Altogether, our data establish that mitochondria, through the regulation of MERCs, controls autophagy that, in turn finely tunes lipid degradation to fuel OxPHOS supporting proliferation and growth in leukemia.


Assuntos
Autofagia/fisiologia , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia/metabolismo , Mitocôndrias/metabolismo , Animais , Autofagia/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Citometria de Fluxo , Humanos , Leucemia/genética , Leucemia Mieloide Aguda/patologia , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Lipogênese/genética , Lipogênese/fisiologia , Camundongos , Mitocôndrias/genética , Oxirredução , Fosforilação Oxidativa
6.
Lancet Haematol ; 7(8): e566-e574, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32735836

RESUMO

BACKGROUND: The median overall survival of patients with high-risk myelodysplastic syndromes refractory to hypomethylating agents is less than 6 months. Currently, no standard therapy for such patients exists. Preclinical studies have shown that inhibition of the nuclear export protein exportin 1 (XPO1) causes nuclear accumulation of p53 and disruption of NF-κB signalling, both relevant targets for myelodysplastic syndromes. We therefore aimed to assess the safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. METHODS: We did a single-centre, single-arm, phase 2 trial at the Memorial Sloan Kettering Cancer Center in the USA. We included patients 18 years or older with high-risk myelodysplastic syndromes or oligoblastic acute myeloid leukaemia (defined as blasts ≥20% but ≤30%) refractory to hypomethylating agents and with an Eastern Cooperative Oncology Group performance status score of 0-2. Eligible patients received 3-week long cycles of oral selinexor (60 mg twice per week for 2 weeks, followed by 1 week off). The primary outcome was overall response rate. Complete remission, partial remission, marrow complete remission, or haematological improvement were included in the response categories for assessing the primary endpoint. The activity analysis included all patients who completed at least one full-scheduled post-treatment disease assessment. All patients who were given selinexor were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT02228525. FINDINGS: Between Sept 23, 2014, and March 13, 2018, 25 patients were enrolled on this study. The median follow-up was 8·5 months (IQR 3·1-12·2). Two patients did not meet the full eligibility criteria after baseline assessment; therefore, 23 patients were evaluable for activity assessment. In the 23 evaluable patients, overall response rate was 26% (95% CI 10-48) in six patients with marrow complete remission, with an additional 12 patients (52%, 95% CI 31-73) achieving stable disease. The most common grade 3 or 4 adverse events were thrombocytopenia (eight [32%] of 25 patients) and hyponatraemia (five [20%]). There were no drug-related serious adverse events and no treatment-related deaths. INTERPRETATION: Selinexor showed responses in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. Adverse events were manageable with supportive care implementation. Further studies are needed to compare selinexor with supportive care alone, and to identify patient subgroups that might benefit the most from selinexor treatment. FUNDING: Karyopharm Therapeutics.


Assuntos
Azacitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Hidrazinas/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Triazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/farmacologia , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Síndromes Mielodisplásicas/patologia , Segurança do Paciente , Prognóstico , Taxa de Sobrevida
7.
Lancet Oncol ; 21(9): 1201-1212, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32791048

RESUMO

BACKGROUND: Findings of retrospective studies suggest that sorafenib maintenance post-transplantation might reduce relapse in patients with FLT3 internal tandem duplication (FLT3-ITD) acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation. We investigated the efficacy and tolerability of sorafenib maintenance post-transplantation in this population. METHODS: We did an open-label, randomised phase 3 trial at seven hospitals in China. Eligible patients (aged 18-60 years) had FLT3-ITD acute myeloid leukaemia, were undergoing allogeneic haematopoietic stem-cell transplantation, had an Eastern Cooperative Oncology Group performance status of 0-2, had composite complete remission before and after transplantation, and had haematopoietic recovery within 60 days post-transplantation. Patients were randomly assigned (1:1) to sorafenib maintenance (400 mg orally twice daily) or non-maintenance (control) at 30-60 days post-transplantation. Randomisation was done with permuted blocks (block size four) and implemented through an interactive web-based randomisation system. The primary endpoint was the 1-year cumulative incidence of relapse in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02474290; the trial is complete. FINDINGS: Between June 20, 2015, and July 21, 2018, 202 patients were enrolled and randomly assigned to sorafenib maintenance (n=100) or control (n=102). Median follow-up post-transplantation was 21·3 months (IQR 15·0-37·0). The 1-year cumulative incidence of relapse was 7·0% (95% CI 3·1-13·1) in the sorafenib group and 24·5% (16·6-33·2) in the control group (hazard ratio 0·25, 95% CI 0·11-0·57; p=0·0010). Within 210 days post-transplantation, the most common grade 3 and 4 adverse events were infections (25 [25%] of 100 patients in the sorafenib group vs 24 [24%] of 102 in the control group), acute graft-versus-host-disease (GVHD; 23 [23%] of 100 vs 21 [21%] of 102), chronic GVHD (18 [18%] of 99 vs 17 [17%] of 99), and haematological toxicity (15 [15%] of 100 vs seven [7%] of 102). There were no treatment-related deaths. INTERPRETATION: Sorafenib maintenance post-transplantation can reduce relapse and is well tolerated in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation. This strategy could be a suitable therapeutic option for patients with FLT3-ITD acute myeloid leukaemia. FUNDING: None.


Assuntos
Doença Enxerto-Hospedeiro/epidemiologia , Leucemia Mieloide Aguda/tratamento farmacológico , Sorafenibe/administração & dosagem , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , China/epidemiologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases , Indução de Remissão , Sorafenibe/efeitos adversos , Sequências de Repetição em Tandem/genética , Transplante Homólogo/efeitos adversos , Adulto Jovem
8.
DNA Cell Biol ; 39(9): 1595-1605, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32783661

RESUMO

Autophagy, a highly conserved cellular protein degradation process, has been involved in acute myeloid leukemia (AML). The present study aims to establish a novel, autophagy-related prognostic signature for prediction of AML prognosis. Differentially expressed autophagy-related genes in AML and healthy samples were screened using GSE1159. Univariate Cox regression analysis was applied to determine survival-associated autophagy-related genes in The Cancer Genome Atlas (TCGA) AML cohort. Lasso regression was performed to develop multiple-gene prognostic signatures. A novel six-gene signature (including CASP3, CHAF1B, KLHL24, OPTN, VEGFA, and VPS37C) DC was established for AML prognosis prediction. The Kaplan-Meier survival analysis revealed that patients in the high-risk score group had poorer overall survival (OS). The receiver operating characteristic (ROC) curve validated its good performance in survival prediction in TCGA AML cohort, and the area under the curve value was 0.817. Moreover, our signature could independently predict OS. A nomogram was constructed, including the six-gene signature and other clinical parameters, and predictive efficiency was confirmed using the ROC curve and calibration curve. Furthermore, gene set enrichment analyses identified several tumor-associated pathways that may contribute to explain the potential molecular mechanisms of our signature. Overall, we developed a new autophagy-associated gene signature and nomogram to predict OS of AML patients, which may help in clinical decision-making for AML treatment.


Assuntos
Autofagia , Biomarcadores Tumorais/genética , Leucemia Mieloide Aguda/genética , Transcriptoma , Biomarcadores Tumorais/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Fator 1 de Modelagem da Cromatina/genética , Fator 1 de Modelagem da Cromatina/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Humanos , Leucemia Mieloide Aguda/patologia , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Proc Natl Acad Sci U S A ; 117(33): 20117-20126, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747558

RESUMO

t(8;21)(q22;q22) acute myelogenous leukemia (AML) is morphologically characterized by a continuum of heterogeneous leukemia cells from myeloblasts to differentiated myeloid elements. Thus, t(8;21) AML is an excellent model for studying heterogeneous cell populations and cellular evolution during disease progression. Using integrative analyses of immunophenotype, RNA-sequencing (RNA-seq), and single-cell RNA-sequencing (scRNA-seq), we identified three distinct intrapatient leukemic cell populations that were arrested at different stages of myeloid differentiation: CD34+CD117dim blasts, CD34+CD117bri blasts, and abnormal myeloid cells with partial maturation (AM). CD117 is also known as c-KIT protein. CD34+CD117dim cells were blocked in the G0/G1 phase at disease onset, presenting with the regular morphology of myeloblasts showing features of granulocyte-monocyte progenitors (GMP), and were drug-resistant to chemotherapy. Genes associated with cell migration and adhesion (LGALS1, EMP3, and ANXA 2) were highly expressed in the CD34+CD117dim population. CD34+CD117bri blasts were blocked a bit later than the CD34+CD117dim population in the hematopoietic differentiation stage and displayed high proliferation ability. AM cells, which bear abnormal myelocyte morphology, especially overexpressed granule genes AZU1, ELANE, and PRTN3 and were sensitive to chemotherapy. scRNA-seq at different time points identified CD34+CD117dim blasts as an important leukemic cluster that expanded at postrelapse refractory stage after several cycles of chemotherapy. Patients with t(8;21) AML with a higher proportion of CD34+CD117dim cells had significantly worse clinical outcomes than those with a lower CD34+CD117dim proportion. Univariate and multivariate analyses identified CD34+CD117dim proportion as an independent factor for poor disease outcome. Our study provides evidence for the multidimensional heterogeneity of t(8;21)AML and may offer new tools for future disease stratification.


Assuntos
Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/patologia , Subpopulações de Linfócitos T/classificação , Subpopulações de Linfócitos T/metabolismo , Adulto , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/metabolismo , Transcriptoma
11.
Cytogenet Genome Res ; 160(5): 255-263, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32544910

RESUMO

Fusions of the Runt-related transcription factor 1 (RUNX1) with different partner genes have been associated with various hematological disorders. Interestingly, the C-terminally truncated form of RUNX1 and RUNX1 fusion proteins are similarly considered important contributors to leukemogenesis. Here, we describe a 59-year-old male patient who was initially diagnosed with acute myeloid leukemia, inv(16)(p13;q22)/CBFB-MYH11 (FAB classification M4Eo). He achieved complete remission and negative CBFB-MYH11 status with daunorubicin/cytarabine combination chemotherapy but relapsed 3 years later. Cytogenetic analysis of relapsed leukemia cells revealed CBFB-MYH11 negativity and complex chromosomal abnormalities without inv(16)(p13;q22). RNA-seq identified the glutamate receptor, ionotropic, kinase 2 (GRIK2) gene on 6q16 as a novel fusion partner for RUNX1 in this case. Specifically, the fusion of RUNX1 to the GRIK2 antisense strand (RUNX1-GRIK2as) generated multiple missplicing transcripts. Because extremely low levels of wild-type GRIK2 were detected in leukemia cells, RUNX1-GRIK2as was thought to drive the pathogenesis associated with the RUNX1-GRIK2 fusion. The truncated RUNX1 generated from RUNX1-GRIK2as induced the expression of the granulocyte colony-stimulating factor (G-CSF) receptor on 32D myeloid leukemia cells and enhanced proliferation in response to G-CSF. In summary, the RUNX1-GRIK2as fusion emphasizes the importance of aberrantly truncated RUNX1 in leukemogenesis.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , DNA Antissenso/genética , Fusão Gênica/genética , Fator Estimulador de Colônias de Granulócitos/farmacologia , Leucemia Mieloide Aguda/genética , Receptores de Ácido Caínico/genética , Deleção de Sequência/genética , Translocação Genética/genética , Proliferação de Células/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , RNA Mensageiro/genética , Receptores de Fator Estimulador de Colônias de Granulócitos/biossíntese , Receptores de Fator Estimulador de Colônias de Granulócitos/metabolismo
12.
Gene ; 755: 144889, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32534056

RESUMO

Ferroptosis, a newly discovered form of non-apoptotic cell death, is induced by an excessive degree of iron-dependent lipid peroxide. ATPR, a novel all-trans retinoic acid (ATRA) derivative, has been extensively developed to show superior anticancer effect than ATRA in acute myeloid leukemia (AML). However, whether ferroptosis exists during ATPR treatment of AML remains unclear. Herein, we found that ferroptosis occurred in an AML xenograft mouse model of ATPR treatment. In vitro, ATPR was verified to induce ferroptosis in a dose-dependent manner by proferroptotic protein marker, lipid peroxidation, and lipid ROS, which could be significantly reversed by ferrostatin-1. Using lysosomal inhibitor chloroquine and iron chelator desferrioxamine, we further revealed that ATPR-induced ferroptosis was regulated by autophagy via iron homeostasis, especially Nrf2. Furthermore, targeting ferroptosis contributes to ATPR-induced AML differentiation. In conclusion, these results indicated that ferroptosis play an important role in ATPR-induced differentiation, and suggested that ATPR would provide a potential therapeutic value for AML treatment.


Assuntos
Ferroptose/efeitos dos fármacos , Leucemia Mieloide Aguda/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Retinoides/farmacologia , Animais , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Homeostase , Humanos , Ferro/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Tretinoína/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Ann Hematol ; 99(7): 1551-1560, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32504186

RESUMO

TP53 aberrations reportedly predict favorable responses to decitabine (DAC) in acute myeloid leukemia (AML). We evaluated clinical features and outcomes associated with chromosome 17p loss or TP53 gene mutations in older, unfit DAC-treated AML patients in a phase II trial. Of 178 patients, 25 had loss of 17p in metaphase cytogenetics; 24 of these had a complex (CK+) and 21 a monosomal karyotype (MK+). In analyses in all patients and restricted to CK+ and MK+ patients, 17p loss tended to associate with higher rates of complete remission (CR), partial remission (PR), or antileukemic effect (ALE). Despite favorable response rates, there was no significant OS difference between patients with or without loss of 17p in the entire cohort or in the CK+ and MK+ cohort. TP53 mutations were identified in eight of 45 patients with material available. Five of the eight TP53-mutated patients had 17p loss. TP53-mutated patients had similar rates of CR/PR/ALE but shorter OS than those with TP53 wild type (P = 0.036). Moreover, patients with a subclone based on mutation data had shorter OS than those without (P = 0.05); only one patient with TP53-mutated AML had a subclone. In conclusion, 17p loss conferred a favorable impact on response rates, even among CK+ and MK+ patients that however could not be maintained. The effect of TP53 mutations appeared to be different; however, patient numbers were low. Future research needs to further dissect the impact of the various TP53 aberrations in HMA-based combination therapies. The limited duration of favorable responses to HMA treatment in adverse-risk genetics AML should prompt physicians to advance allografting for eligible patients in a timely fashion.


Assuntos
Deleção Cromossômica , Decitabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Monossomia , Síndrome de Smith-Magenis , Proteína Supressora de Tumor p53/genética , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 17/genética , Evolução Clonal/efeitos dos fármacos , Evolução Clonal/genética , Análise Mutacional de DNA , Feminino , Alemanha/epidemiologia , Humanos , Cariótipo , Cariotipagem , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Monossomia/diagnóstico , Monossomia/genética , Mutação , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/epidemiologia , Síndrome de Smith-Magenis/genética , Análise de Sobrevida
14.
Middle East Afr J Ophthalmol ; 27(1): 56-58, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32549726

RESUMO

Sub-internal limiting membrane (sub-ILM) hemorrhage is a distinct type of retinal hemorrhage in which the blood accumulates between ILM and nerve fiber layer. Little is known about visual prognosis as well as ideal management of foveal sub-ILM hemorrhage in patients with acute leukemia. Herein, we presented a case of acute myeloid leukemia with foveal sub-ILM hemorrhage. Observation alone resulted in complete resolution of hemorrhage with good visual and anatomical outcome.


Assuntos
Membrana Basal/fisiopatologia , Leucemia Mieloide Aguda/patologia , Fibras Nervosas/patologia , Hemorragia Retiniana/fisiopatologia , Acuidade Visual/fisiologia , Adulto , Membrana Basal/diagnóstico por imagem , Humanos , Masculino , Prognóstico , Remissão Espontânea , Hemorragia Retiniana/diagnóstico por imagem , Tomografia de Coerência Óptica , Vitrectomia/métodos
15.
Eur J Med Chem ; 200: 112338, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32497960

RESUMO

Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemical and biophysical tests showed that compounds 23a,b and 37 are nanomolar inhibitors of both target proteins. Detailed structure-activity relationships were deduced for the synthesized inhibitors which were supported by extensive docking and molecular dynamics studies. Cellular testing in acute myeloid leukemia (AML) cells showed only a weak effect, most probably because of the poor permeability of the inhibitors. We also aimed to analyse the target engagement and the cellular activity of the novel inhibitors by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Antineoplásicos/síntese química , Proteínas de Ligação a DNA/antagonistas & inibidores , Desenho de Fármacos , Desacetilase 6 de Histona/antagonistas & inibidores , Proteínas Repressoras/antagonistas & inibidores , Acetilação/efeitos dos fármacos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade
16.
BMC Infect Dis ; 20(1): 404, 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32517658

RESUMO

BACKGROUND: Carbapenem is frequently used when gram negative bacilli (GNB) bacteremia is detected especially in neutropenic patients. Consequently, appropriate treatment could be delayed in GNB bacteremia cases involving organisms which are not susceptible to carbapenem (carba-NS), resulting in a poor clinical outcomes. Here, we explored risk factors for carba-NS GNB bacteremia and its clinical outcomes in patients with acute myelogenous leukemia (AML) that underwent chemotherapy. METHODS: We reviewed all GNB bacteremia cases that occurred during induction or consolidation chemotherapy, over a 15-year period, in a tertiary-care hospital. RESULTS: Among 489 GNB bacteremia cases from 324 patients, 45 (9.2%) were carba-NS and 444 (90.8%) were carbapenem susceptible GNB. Independent risk factors for carba-NS GNB bacteremia were: carbapenem use at bacteremia onset (adjusted odds ratio [aOR]: 91.2; 95% confidence interval [95%CI]: 29.3-284.1; P < 0.001); isolation of carbapenem-resistant Acinetobacter baumannii (aOR: 19.4, 95%CI: 3.4-112.5; P = 0.001) in the prior year; and days from chemotherapy to GNB bacteremia (aOR: 1.1 per day, 95%CI: 1.1-1.2; P < 0.001). Carba-NS bacteremia was independently associated with in-hospital mortality (aOR: 6.6, 95%CI: 3.0-14.8; P < 0.001). CONSLUSION: Carba-NS organisms should be considered for antibiotic selection in AML patients having these risk factors.


Assuntos
Farmacorresistência Bacteriana , Infecções por Bactérias Gram-Negativas/diagnóstico , Leucemia Mieloide Aguda/patologia , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/isolamento & purificação , Adulto , Idoso , Antibacterianos/farmacologia , Antineoplásicos/uso terapêutico , Carbapenêmicos/farmacologia , Estudos de Casos e Controles , Feminino , Infecções por Bactérias Gram-Negativas/complicações , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Negativas/mortalidade , Mortalidade Hospitalar , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Retrospectivos , Fatores de Risco , Centros de Atenção Terciária , Resultado do Tratamento
17.
J Cancer Res Ther ; 16(1): 18-22, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362604

RESUMO

Introduction and Aims: Acute myeloid leukemia (AML) in adults has poor prognosis. The epidemiologic profile of patients varies greatly in different geographic locations and so do the cytogenetic abnormalities and the FAB subtype of the AML. We intended to study the clinical profile, cytogenetics, and outcomes with standard of care treatment on our population in India. Methods: This was a retrospective study with systematic review of 203 case records. Primary objectives were to know the demographic profile of AML, prevalence of various FAB subtypes, cytogenetic abnormalities, and treatment outcomes at our center, which is a referral center of oncology. Two treatment outcomes considered in study for patients of AML were achievement of remission status of the bone marrow postintensive induction chemotherapy and sustenance of the remission for 6 months, once remission is achieved. Secondary objective was to study these outcomes in non-M3 AML in relation to cytogenetics. Results: Median age was 39 years. The most common FAB subtype observed was AML M2. About 65.6% patients achieved complete remission (CR), and 42.4% patients could sustain it for next 6 months. Cytogenetics correlated with prognosis but not age. Conclusions: Our population differs from the Western population regarding lower age, lower prevalence of adverse cytogenetics, and higher prevalence of favorable cytogenetic abnormalities. Cytogenetics had a good correlation with CR rates after chemotherapy as well as its sustenance.


Assuntos
Medula Óssea/patologia , Aberrações Cromossômicas , Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Índia , Cariotipagem/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
18.
J Cancer Res Ther ; 16(1): 23-27, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362605

RESUMO

Objective: Growth factor independence 1 (GFI1), a transcriptional repressor, is required for hematopoietic stem cell maintenance and self-renewal in addition to controlling differentiation and proliferation of myeloid cells. As murine studies have demonstrated that this transcription factor has a notable role in the initiation and progression of acute myeloid leukemia (AML) disease, the aim of the current study was to investigate and review the influence of GFI1 in human AML cells. Methods: GFI1 expression levels were measured by means of real-time polymerase chain reaction in 96 primary AML samples which were then compared to gene expression levels observed in 18 healthy subjects. Moreover, GFI1 expression patterns were analyzed based on specific AML subtypes including acute promyelocytic leukemia (APL). Finally, leukemic cells were stained to measure levels of myeloperoxidase (MPO) activity. Results: This study reports that AML patients have significantly higher GFI1 mRNA levels in comparison to healthy subjects and that, when considering AML subtypes, patients with APL have higher GFI1 expression than non-APL patients. Conclusion: It is also concluded that GFI1 overexpression in patients with high MPO levels, such as those of the APL subtype, is correlated with favorable disease prognosis as supported by other studies which demonstrate that increased peroxide activity and GFI1 are independently correlated with a favorable prognosis.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Promielocítica Aguda/metabolismo , Fatores de Transcrição/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Transcrição/genética , Adulto Jovem
19.
J Cancer Res Ther ; 16(1): 105-109, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362618

RESUMO

Background: Aberrant phenotypes in acute leukemia have been reported with varying frequencies in independent studies and their association with prognostic factors is still a matter of debate. Aim: This study aims to identify the frequency of aberrant immunophenotypes in de novo acute myeloid leukemia (AML) and to evaluate their association with initial clinical and hematological features. Materials and Methods: A total of 181 patients of de novo AML were included during the time (July 2010-June 2012). The immunophenotype of all cases of AML was studied by using flow cytometry. Results: Aberrant lymphoid antigen expression was seen in 43.1% cases. Most frequent aberrant lymphoid antigen was CD7, seen in 26.5% cases. All French-American-British (FAB) subtypes except AML-M3 expressed aberrant lymphoid antigens. The expression was most common in AML-M4 in the current study. CD34 expression in AMLs was significantly associated with the expression of aberrant lymphoid antigens. Lymphoid antigen expression in adult AML was significantly associated with higher white blood cell (WBC) count (>50,000/mm3) and higher number of peripheral blasts (>70%). Conclusion: In summary, CD7 is the most common aberrant lymphoid antigen expressed in AML. FAB subtype AML-M3 is usually not associated with aberrant lymphoid antigen expression. AML cases with CD34 positivity are more likely to express aberrant lymphoid markers. The current study also supports that aberrant lymphoid antigen expression in adult AML is associated with adverse presenting hematological features (WBC count >50,000/mm3, peripheral blasts >70%). Pediatric Ly + AML cases are not associated with adverse presenting clinical and biological features.


Assuntos
Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais/imunologia , Imunofenotipagem/métodos , Leucemia Mieloide Aguda/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/imunologia , Antígenos CD34/metabolismo , Antígenos CD7/imunologia , Antígenos CD7/metabolismo , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Prognóstico , Estudos Prospectivos , Centros de Atenção Terciária , Adulto Jovem
20.
Proc Natl Acad Sci U S A ; 117(22): 12332-12340, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32424097

RESUMO

Double knockout of the two miR-15/16 loci in mouse resulted in the development of acute myeloid leukemia (AML). This result suggested that, at least, a fraction of human AMLs could be due to a similar mechanism. We analyzed the role of the two miR-15/16 clusters in 93 myelodysplastic syndrome (MDS) patients divided in three subgroups: patients with MDS, patients with MDS before transforming into AML (MDS-T), and patients with AML evolving from MDS (MDS-AML). Then, we tested 139 AML cases and 14 different AML cell lines by assessing microRNA (miRNA) expression, target protein expression, genetic loss, and silencing. MDS-T and MDS-AML patients show a reduction of the expression of miR-15a/-15b/-16 compared to MDS patients. Each miRNA can significantly predict MDS and MDS-T groups. Then, 79% of primary AMLs show a reduced expression of miR-15a and/or miR-15b. The expression of miR-15a/-15b/-16 significantly stratified AML patients in two prognostic classes. Furthermore, 40% of AML cell lines showed a combined loss of the expression of miR-15a/-15b and overexpression of their direct/indirect targets. As potential mechanisms involved in the silencing of the two miR-15/16 loci, we identified a genetic loss of miR-15a and miR-15b and silencing of these two loci by methylation. We identified a potential driver oncogenic role in the loss of expression of both miR-15/16 clusters in the progression of MDS into AML and in AML pathogenesis. The stratification of AML patients, based on miR-15/16 expression, can lead to targeted and combination therapies for the treatment of this incurable disease.


Assuntos
Leucemia Mieloide Aguda/genética , MicroRNAs/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Progressão da Doença , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade
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