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1.
Blood ; 125(8): 1292-301, 2015 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-25533034

RESUMO

Children with Down syndrome (DS) are at increased risk for acute myeloid leukemias (ML-DS) characterized by mixed megakaryocytic and erythroid phenotype and by acquired mutations in the GATA1 gene resulting in a short GATA1s isoform. The chromosome 21 microRNA (miR)-125b cluster has been previously shown to cooperate with GATA1s in transformation of fetal hematopoietic progenitors. In this study, we report that the expression of miR-486-5p is increased in ML-DS compared with non-DS acute megakaryocytic leukemias (AMKLs). miR-486-5p is regulated by GATA1 and GATA1s that bind to the promoter of its host gene ANK1. miR-486-5p is highly expressed in mouse erythroid precursors and knockdown (KD) in ML-DS cells reduced their erythroid phenotype. Ectopic expression and KD of miR-486-5p in primary fetal liver hematopoietic progenitors demonstrated that miR-486-5p cooperates with Gata1s to enhance their self renewal. Consistent with its activation of AKT, overexpression and KD experiments showed its importance for growth and survival of human leukemic cells. Thus, miR-486-5p cooperates with GATA1s in supporting the growth and survival, and the aberrant erythroid phenotype of the megakaryocytic leukemias of DS.


Assuntos
Síndrome de Down/genética , Eritropoese/genética , Leucemia Mieloide Aguda/genética , MicroRNAs/fisiologia , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Pré-Escolar , Síndrome de Down/complicações , Síndrome de Down/fisiopatologia , Células Eritroides/metabolismo , Células HEK293 , Humanos , Células K562 , Leucemia Mieloide Aguda/patologia , Megacariócitos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , Células Tumorais Cultivadas
2.
Haematologica ; 100(5): 575-84, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25682601

RESUMO

GATA1 is a master transcriptional regulator of the differentiation of several related myeloid blood cell types, including erythrocytes and megakaryocytes. Germ-line mutations that cause loss of full length GATA1, but allow for expression of the short isoform (GATA1s), are associated with defective erythropoiesis in a subset of patients with Diamond Blackfan Anemia. Despite extensive studies of GATA1s in megakaryopoiesis, the mechanism by which GATA1s fails to support normal erythropoiesis is not understood. In this study, we used global gene expression and chromatin occupancy analysis to compare the transcriptional activity of GATA1s to GATA1. We discovered that compared to GATA1, GATA1s is less able to activate the erythroid gene expression program and terminal differentiation in cells with dual erythroid-megakaryocytic differentiation potential. Moreover, we found that GATA1s bound to many of its erythroid-specific target genes less efficiently than full length GATA1. These results suggest that the impaired ability of GATA1s to promote erythropoiesis in DBA may be caused by failure to occupy erythroid-specific gene regulatory elements.


Assuntos
Imunoprecipitação da Cromatina , Células Eritroides/metabolismo , Fator de Transcrição GATA1/genética , Regulação da Expressão Gênica , Isoformas de RNA , Transcriptoma , Sítios de Ligação , Diferenciação Celular/genética , Linhagem Celular , Análise por Conglomerados , Células Eritroides/citologia , Eritropoese/genética , Fator de Transcrição GATA1/metabolismo , Perfilação da Expressão Gênica , Humanos , Megacariócitos/citologia , Megacariócitos/metabolismo , Motivos de Nucleotídeos , Ligação Proteica , Trombopoese/genética
3.
Artigo em Inglês | MEDLINE | ID: mdl-31548219

RESUMO

Acute megakaryoblastic leukemia (AMKL) is a rare malignancy affecting megakaryocytes, platelet-producing cells that reside in the bone marrow. Children with Down syndrome (DS) are particularly prone to developing the disease and have a different age of onset, distinct genetic mutations, and better prognosis as compared with individuals without DS who develop the disease. Here, we discuss the contributions of chromosome 21 genes and other genetic mutations to AMKL, the clinical features of the disease, and the differing features of DS- and non-DS-AMKL. Further studies elucidating the role of chromosome 21 genes in this disease may aid our understanding of how they function in other types of leukemia, in which they are frequently mutated or differentially expressed. Although researchers have made many insights into understanding AMKL, much more remains to be learned about its underlying molecular mechanisms.


Assuntos
Síndrome de Down/complicações , Síndrome de Down/genética , Leucemia Megacarioblástica Aguda/etiologia , Leucemia Megacarioblástica Aguda/genética , Animais , Criança , Fator de Transcrição GATA1/genética , Humanos , Mutação
4.
Trends Cancer ; 3(4): 282-293, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28626802

RESUMO

Acute Myeloid Leukemia (AML) is a hematologic malignancy with a poor prognosis. Recent genome-wide sequencing studies have identified frequent mutations in genes encoding members of the cohesin complex. Mutations in cohesin contribute to myeloid malignancies by conferring enhanced self-renewal of hematopoietic stem and progenitor cells but the mechanisms behind this phenotype have not been fully elucidated. Of note, cohesin mutations are highly prevalent in acute megakaryocytic leukemia associated with Down syndrome (DS-AMKL), where they occur in over half of patients. Evidence suggests that cohesin mutations alter gene expression through changes in chromatin accessibility and/or aberrant targeting of epigenetic complexes. In this review we discuss the pathogenic mechanisms by which cohesin mutations contribute to myeloid malignancies.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Leucemia Mieloide Aguda/genética , Humanos , Mutação , Coesinas
5.
Cell Metab ; 25(1): 86-92, 2017 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-27773696

RESUMO

Circadian clocks are encoded by a transcription-translation feedback loop that aligns energetic processes with the solar cycle. We show that genetic disruption of the clock activator BMAL1 in skeletal myotubes and fibroblasts increased levels of the hypoxia-inducible factor 1α (HIF1α) under hypoxic conditions. Bmal1-/- myotubes displayed reduced anaerobic glycolysis, mitochondrial respiration with glycolytic fuel, and transcription of HIF1α targets Phd3, Vegfa, Mct4, Pk-m, and Ldha, whereas abrogation of the clock repressors CRY1/2 stabilized HIF1α in response to hypoxia. HIF1α bound directly to core clock gene promoters, and, when co-expressed with BMAL1, led to transactivation of PER2-LUC and HRE-LUC reporters. Further, genetic stabilization of HIF1α in Vhl-/- cells altered circadian transcription. Finally, induction of clock and HIF1α target genes in response to strenuous exercise varied according to the time of day in wild-type mice. Collectively, our results reveal bidirectional interactions between circadian and HIF pathways that influence metabolic adaptation to hypoxia.


Assuntos
Relógios Circadianos , Glicólise , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Músculo Esquelético/metabolismo , Oxigênio/metabolismo , Anaerobiose , Animais , Relógios Circadianos/genética , Ritmo Circadiano/genética , Hipóxia/genética , Hipóxia/metabolismo , Camundongos , Especificidade de Órgãos , Consumo de Oxigênio , Condicionamento Físico Animal , Transcrição Gênica
6.
J Clin Invest ; 127(4): 1316-1320, 2017 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-28240607

RESUMO

Primary myelofibrosis (PMF) is a clonal hematologic malignancy characterized by BM fibrosis, extramedullary hematopoiesis, circulating CD34+ cells, splenomegaly, and a propensity to evolve to acute myeloid leukemia. Moreover, the spleen and BM of patients harbor atypical, clustered megakaryocytes, which contribute to the disease by secreting profibrotic cytokines. Here, we have revealed that megakaryocytes in PMF show impaired maturation that is associated with reduced GATA1 protein. In investigating the cause of GATA1 downregulation, our gene-expression study revealed the presence of the RPS14-deficient gene signature, which is associated with defective ribosomal protein function and linked to the erythroid lineage in 5q deletion myelodysplastic syndrome. Surprisingly, reduced GATA1 expression and impaired differentiation were limited to megakaryocytes, consistent with a proproliferative effect of a GATA1 deficiency on this lineage. Importantly, expression of GATA1 effectively rescued maturation of PMF megakaryocytes. Together, these results suggest that ribosomal deficiency contributes to impaired megakaryopoiesis in myeloproliferative neoplasms.


Assuntos
Regulação para Baixo , Fator de Transcrição GATA1/biossíntese , Megacariócitos/metabolismo , Mielofibrose Primária/metabolismo , Trombopoese , Animais , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 5/metabolismo , Fator de Transcrição GATA1/genética , Humanos , Megacariócitos/patologia , Camundongos , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Proteínas Ribossômicas/biossíntese , Proteínas Ribossômicas/genética
7.
Cell Stem Cell ; 18(5): 563-4, 2016 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-27152438

RESUMO

GATA1 mutations and trisomy 21 are inextricably linked in the neonatal leukemia of children with Down syndrome (DS). A recent report by Banno et al. (2016) sheds new light on the mechanism of the synergy between these genetic alterations by modeling hematopoietic abnormalities with patient-derived induced pluripotent stem cells.


Assuntos
Síndrome de Down/genética , Fator de Transcrição GATA1/genética , Humanos , Células-Tronco Pluripotentes Induzidas , Mutação
8.
Clin Cancer Res ; 22(10): 2396-404, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-26671993

RESUMO

PURPOSE: Identification of predictive biomarkers is critically needed to improve selection of patients who derive the most benefit from platinum-based chemotherapy. We hypothesized that decreased expression of SMARCA4/BRG1, a known regulator of transcription and DNA repair, is a novel predictive biomarker of increased sensitivity to adjuvant platinum-based therapies in non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: The prognostic value was tested using a gene-expression microarray from the Director's Challenge Lung Study (n = 440). The predictive significance of SMARCA4 was determined using a gene-expression microarray (n = 133) from control and treatment arms of the JBR.10 trial of adjuvant cisplatin/vinorelbine. Kaplan-Meier method and log-rank tests were used to estimate and test the differences of probabilities in overall survival (OS) and disease-specific survival (DSS) between expression groups and treatment arms. Multivariate Cox regression models were used while adjusting for other clinical covariates. RESULTS: In the Director's Challenge Study, reduced expression of SMARCA4 was associated with poor OS compared with high and intermediate expression (P < 0.001 and P = 0.009, respectively). In multivariate analysis, compared with low, high SMARCA4 expression predicted a decrease in risk of death [HR, 0.6; 95% confidence interval (CI), 0.4-0.8; P = 0.002]. In the JBR.10 trial, improved 5-year DSS was noted only in patients with low SMARCA4 expression when treated with adjuvant cisplatin/vinorelbine [HR, 0.1; 95% CI, 0.0-0.5, P = 0.002 (low); HR, 1.0; 95% CI, 0.5-2.3, P = 0.92 (high)]. An interaction test was highly significant (P = 0.01). CONCLUSIONS: Low expression of SMARCA4/BRG1 is significantly associated with worse prognosis; however, it is a novel significant predictive biomarker for increased sensitivity to platinum-based chemotherapy in NSCLC. Clin Cancer Res; 22(10); 2396-404. ©2015 AACR.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Cisplatino/uso terapêutico , DNA Helicases/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Vimblastina/análogos & derivados , Vimblastina/uso terapêutico , Vinorelbina
9.
PLoS One ; 10(3): e0118745, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25760964

RESUMO

PURPOSE: To develop a microRNA (miRNA)-based predictive model for prostate cancer patients of 1) time to biochemical recurrence after radical prostatectomy and 2) biochemical recurrence after salvage radiation therapy following documented biochemical disease progression post-radical prostatectomy. METHODS: Forty three patients who had undergone salvage radiation therapy following biochemical failure after radical prostatectomy with greater than 4 years of follow-up data were identified. Formalin-fixed, paraffin-embedded tissue blocks were collected for all patients and total RNA was isolated from 1mm cores enriched for tumor (>70%). Eight hundred miRNAs were analyzed simultaneously using the nCounter human miRNA v2 assay (NanoString Technologies; Seattle, WA). Univariate and multivariate Cox proportion hazards regression models as well as receiver operating characteristics were used to identify statistically significant miRNAs that were predictive of biochemical recurrence. RESULTS: Eighty eight miRNAs were identified to be significantly (p<0.05) associated with biochemical failure post-prostatectomy by multivariate analysis and clustered into two groups that correlated with early (≤ 36 months) versus late recurrence (>36 months). Nine miRNAs were identified to be significantly (p<0.05) associated by multivariate analysis with biochemical failure after salvage radiation therapy. A new predictive model for biochemical recurrence after salvage radiation therapy was developed; this model consisted of miR-4516 and miR-601 together with, Gleason score, and lymph node status. The area under the ROC curve (AUC) was improved to 0.83 compared to that of 0.66 for Gleason score and lymph node status alone. CONCLUSION: miRNA signatures can distinguish patients who fail soon after radical prostatectomy versus late failures, giving insight into which patients may need adjuvant therapy. Notably, two novel miRNAs (miR-4516 and miR-601) were identified that significantly improve prediction of biochemical failure post-salvage radiation therapy compared to clinico-histopathological factors, supporting the use of miRNAs within clinically used predictive models. Both findings warrant further validation studies.


Assuntos
Biomarcadores Tumorais/metabolismo , MicroRNAs/metabolismo , Neoplasias da Próstata/metabolismo , Idoso , Área Sob a Curva , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-Idade , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Curva ROC , Terapia de Salvação , Falha de Tratamento
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