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1.
Zhonghua Xue Ye Xue Za Zhi ; 42(1): 45-51, 2021 Jan 14.
Artigo em Chinês | MEDLINE | ID: mdl-33677868

RESUMO

Objective: To investigate the clinical features and prognosis of ETV6-RUNX1-positive childhood B-precursor acute lymphocyte leukemia (B-ALL) . Methods: The clinical data of 927 newly diagnosed children with B-ALL admitted to the Fujian Medical University Union Hospital from April 2011 to May 2020 were retrospectively analyzed. According to the results of ETV6-RUNX1 gene, the patients were divided into ETV6-RUNX1(+) and ETV6-RUNX1(-) groups. The clinical features and prognosis between the two groups were compared. Among the 182 children with ETV6-RUNX1(+), 144 patients received the Chinese Childhood Leukemia Collaborative Group (CCLG) -ALL 2008 protocol (CCLG-ALL 2008 group) and 38 received the China Childhood Cancer Collaborative Group (CCCG) -ALL2015 protocol (CCCG-ALL 2015 group) . The efficacy, serious adverse effects (SAE) incidence, and treatment-related mortality (TRM) of the two groups were also compared. Results: Of the 927 B-ALL patients, 189 (20.4% ) were ETV6-RUNX1(+). The proportion of patients with risk factors (age ≥10 years or <1 year, white blood cell count ≥50×10(9)/L) in the ETV6-RUNX1(+) group was significantly lower than that in the ETV6-RUNX1(-) group (P=0.000, 0.001, respectively) , while the proportion of patients with good early response (good response to prednisone, d15 or d19 MRD <1% , and d33 or d46 MRD<0.01% in induction chemotherapy) in the ETV6-RUNX1(+) group was significantly higher than that in the ETV6-RUNX1(-) group (P=0.028, 0.004, respectively) . The 5-year EFS and OS of the ETV6-RUNX1(+) group were significantly higher than those of the ETV6-RUNX1(-) group (EFS: 89.8% vs 83.2% , P=0.003; OS: 90.2% vs 86.3% , P=0.030) . The incidence of infection-related SAE and TRM was significantly higher than that of CCCG-ALL 2015 group. A statistical difference was observed between the incidence of infection-related SAE of the two groups (27.1% vs 5.3% , P=0.004) , but no difference in TRM (4.9% vs 0, P=0.348) . Conclusion: ETV6-RUNX1(+)B-ALL children have fewer risk factors at diagnosis, better early response, lower recurrence rate, and good prognosis than that of ETV6-RUNX1(-)B-ALL children. Reducing the intensity of chemotherapy appropriately can lower the infection-related SAE and TRM and improve the long-term survival in this subtype.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Linfócitos , Criança , China , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Intervalo Livre de Doença , Humanos , Proteínas de Fusão Oncogênica/genética , Prognóstico , Estudos Retrospectivos
2.
Nat Commun ; 12(1): 821, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547282

RESUMO

Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10-8) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells (P < 0.0001). The top two differentially methylated regions overlap RUNX1 and FLI1, both important regulators of megakaryopoiesis and hematopoietic development, with significant hypermethylation at promoter regions of these two genes. Excluding Down syndrome newborns harboring preleukemic GATA1 mutations (N = 30), identified by targeted sequencing, has minimal impact on the epigenome-wide association study results. Down syndrome has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with Down syndrome.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Síndrome de Down/genética , Epigênese Genética , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Proteína Proto-Oncogênica c-fli-1/genética , Estudos de Casos e Controles , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Ilhas de CpG , Metilação de DNA , Síndrome de Down/metabolismo , Síndrome de Down/patologia , Feminino , Feto , Fator de Transcrição GATA1/genética , Fator de Transcrição GATA1/metabolismo , Genoma Humano , Estudo de Associação Genômica Ampla , Células-Tronco Hematopoéticas/patologia , Humanos , Recém-Nascido , Fígado/metabolismo , Fígado/patologia , Masculino , Regiões Promotoras Genéticas , Proteína Proto-Oncogênica c-fli-1/metabolismo
3.
Mol Cell ; 81(3): 418-420, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33545056

RESUMO

Transcription factors (TFs) are frequently altered in human diseases. Identifying the direct and immediate target genes of TFs is critical to understanding their role in pathophysiology. Stengel et al. (2020) applied chemogenetic and nascent transcriptome mapping technologies to define the core gene set regulated by AML1-ETO-an oncogenic TF fusion protein frequently found in acute myeloid leukemia (AML).


Assuntos
Socorristas , Leucemia Mieloide Aguda , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Humanos , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Translocação Genética
4.
Nat Commun ; 12(1): 1026, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33589589

RESUMO

Proprioceptive neurons (PNs) are essential for the proper execution of all our movements by providing muscle sensory feedback to the central motor network. Here, using deep single cell RNAseq of adult PNs coupled with virus and genetic tracings, we molecularly identify three main types of PNs (Ia, Ib and II) and find that they segregate into eight distinct subgroups. Our data unveil a highly sophisticated organization of PNs into discrete sensory input channels with distinct spatial distribution, innervation patterns and molecular profiles. Altogether, these features contribute to finely regulate proprioception during complex motor behavior. Moreover, while Ib- and II-PN subtypes are specified around birth, Ia-PN subtypes diversify later in life along with increased motor activity. We also show Ia-PNs plasticity following exercise training, suggesting Ia-PNs are important players in adaptive proprioceptive function in adult mice.


Assuntos
Retroalimentação Sensorial/fisiologia , Gânglios Espinais/metabolismo , Neurônios Motores/metabolismo , Propriocepção/fisiologia , Células Receptoras Sensoriais/metabolismo , Animais , Calbindina 1/genética , Calbindina 1/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Gânglios Espinais/citologia , Expressão Gênica , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios Motores/classificação , Neurônios Motores/citologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Condicionamento Físico Animal , Células Receptoras Sensoriais/classificação , Células Receptoras Sensoriais/citologia , Análise de Célula Única , Medula Espinal/citologia , Medula Espinal/metabolismo
5.
Nat Cell Biol ; 23(1): 61-74, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33420489

RESUMO

Extra-embryonic mesoderm (ExM)-composed of the earliest cells that traverse the primitive streak-gives rise to the endothelium as well as haematopoietic progenitors in the developing yolk sac. How a specific subset of ExM becomes committed to a haematopoietic fate remains unclear. Here we demonstrate using an embryonic stem cell model that transient expression of the T-box transcription factor Eomesodermin (Eomes) governs haemogenic competency of ExM. Eomes regulates the accessibility of enhancers that the transcription factor stem cell leukaemia (SCL) normally utilizes to specify primitive erythrocytes and is essential for the normal development of Runx1+ haemogenic endothelium. Single-cell RNA sequencing suggests that Eomes loss of function profoundly blocks the formation of blood progenitors but not specification of Flk-1+ haematoendothelial progenitors. Our findings place Eomes at the top of the transcriptional hierarchy regulating early blood formation and suggest that haemogenic competence is endowed earlier during embryonic development than was previously appreciated.


Assuntos
Células-Tronco Embrionárias/citologia , Hemangioblastos/citologia , Mesoderma/citologia , Proteínas com Domínio T/fisiologia , Saco Vitelino/citologia , Animais , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Células-Tronco Embrionárias/metabolismo , Feminino , Hemangioblastos/metabolismo , Masculino , Mesoderma/metabolismo , Camundongos Knockout , Gravidez , RNA-Seq , Análise de Célula Única , Proteína 1 de Leucemia Linfocítica Aguda de Células T/genética , Proteína 1 de Leucemia Linfocítica Aguda de Células T/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Saco Vitelino/metabolismo
6.
Lancet Haematol ; 8(3): e194-e204, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33508247

RESUMO

BACKGROUND: Several risk stratification models have been proposed in recent years for systemic mastocytosis but have not been directly compared. Here we designed and validated a risk stratification model for progression-free survival (PFS) and overall survival (OS) in systemic mastocytosis on the basis of all currently available prognostic factors, and compared its predictive capacity for patient outcome with that of other risk scores. METHODS: We did a retrospective prognostic modelling study based on patients diagnosed with systemic mastocytosis between March 1, 1983, and Oct 11, 2019. In a discovery cohort of 422 patients from centres of the Spanish Network on Mastocytosis (REMA), we evaluated previously identified, independent prognostic features for prognostic effect on PFS and OS by multivariable analysis, and designed a global prognostic score for mastocytosis (GPSM) aimed at predicting PFS (GPSM-PFS) and OS (GPSM-OS) by including only those variables that showed independent prognostic value (p<0·05). The GPSM scores were validated in an independent cohort of 853 patients from centres in Europe and the USA, and compared with pre-existing risk models in the total patient series (n=1275), with use of Harrells' concordance index (C-index) as a readout of the ability of each model to risk-stratify patients according to survival outcomes. FINDINGS: Our GPSM-PFS and GPSM-OS models were based on unique combinations of independent prognostic factors for PFS (platelet count ≤100 × 109 cells per L, serum ß2-microglobulin ≥2·5 µg/mL, and serum baseline tryptase ≥125 µg/L) and OS (haemoglobin ≤110 g/L, serum alkaline phosphatase ≥140 IU/L, and at least one mutation in SRSF2, ASXL1, RUNX1, or DNMT3A). The models showed clear discrimination between low-risk and high-risk patients in terms of worse PFS and OS prognoses in the discovery and validation cohorts, and further discrimination of intermediate-risk patients. The GPSM-PFS score was an accurate predictor of PFS in systemic mastocytosis (C-index 0·90 [95% CI 0·87-0·93], vs values ranging from 0·85 to 0·88 for pre-existing models), particularly in non-advanced systemic mastocytosis (C-index 0·85 [0·76-0·92], within the range for pre-existing models of 0·80 to 0·93). Additionally, the GPSM-OS score was able to accurately predict OS in the entire cohort (C-index 0·92 [0·89-0·94], vs 0·67 to 0·90 for pre-existing models), and showed some capacity to predict OS in advanced systemic mastocytosis (C-index 0·72 [0·66-0·78], vs 0·64 to 0·73 for pre-existing models). INTERPRETATION: All evaluated risk classifications predicted survival outcomes in systemic mastocytosis. The REMA-PFS and GPSM-PFS models for PFS, and the International Prognostic Scoring System for advanced systemic mastocytosis and GPSM-OS model for OS emerged as the most accurate models, indicating that robust prognostication might be prospectively achieved on the basis of biomarkers that are accessible in diagnostic laboratories worldwide. FUNDING: Carlos III Health Institute, European Regional Development Fund, Spanish Association of Mastocytosis and Related Diseases, Rare Diseases Strategy of the Spanish National Health System, Junta of Castile and León, Charles and Ann Johnson Foundation, Stanford Cancer Institute Innovation Fund, Austrian Science Fund.


Assuntos
Mastocitose Sistêmica/diagnóstico , Adulto , Idoso , Fosfatase Alcalina/sangue , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Hemoglobinas/análise , Humanos , Estimativa de Kaplan-Meier , Masculino , Mastocitose Sistêmica/mortalidade , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Intervalo Livre de Progressão , Proteínas Repressoras/genética , Estudos Retrospectivos , Fatores de Risco , Fatores de Processamento de Serina-Arginina/genética
7.
PLoS Genet ; 17(1): e1009233, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33476325

RESUMO

Runx1 is highly expressed in osteoblasts, however, its function in osteogenesis is unclear. We generated mesenchymal progenitor-specific (Runx1f/fTwist2-Cre) and osteoblast-specific (Runx1f/fCol1α1-Cre) conditional knockout (Runx1 CKO) mice. The mutant CKO mice with normal skeletal development displayed a severe osteoporosis phenotype at postnatal and adult stages. Runx1 CKO resulted in decreased osteogenesis and increased adipogenesis. RNA-sequencing analysis, Western blot, and qPCR validation of Runx1 CKO samples showed that Runx1 regulates BMP signaling pathway and Wnt/ß-catenin signaling pathway. ChIP assay revealed direct binding of Runx1 to the promoter regions of Bmp7, Alk3, and Atf4, and promoter mapping demonstrated that Runx1 upregulates their promoter activity through the binding regions. Bmp7 overexpression rescued Alk3, Runx2, and Atf4 expression in Runx1-deficient BMSCs. Runx2 expression was decreased while Runx1 was not changed in Alk3 deficient osteoblasts. Atf4 overexpression in Runx1-deficient BMSCs did not rescue expression of Runx1, Bmp7, and Alk3. Smad1/5/8 activity was vitally reduced in Runx1 CKO cells, indicating Runx1 positively regulates the Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 signaling pathway. Notably, Runx1 overexpression in Runx2-/- osteoblasts rescued expression of Atf4, OCN, and ALP to compensate Runx2 function. Runx1 CKO mice at various osteoblast differentiation stages reduced Wnt signaling and caused high expression of C/ebpα and Pparγ and largely increased adipogenesis. Co-culture of Runx1-deficient and wild-type cells demonstrated that Runx1 regulates osteoblast-adipocyte lineage commitment both cell-autonomously and non-autonomously. Notably, Runx1 overexpression rescued bone loss in OVX-induced osteoporosis. This study focused on the role of Runx1 in different cell populations with regards to BMP and Wnt signaling pathways and in the interacting network underlying bone homeostasis as well as adipogenesis, and has provided new insight and advancement of knowledge in skeletal development. Collectively, Runx1 maintains adult bone homeostasis from bone loss though up-regulating Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 and WNT/ß-Catenin signaling pathways, and targeting Runx1 potentially leads to novel therapeutics for osteoporosis.


Assuntos
Proteína Morfogenética Óssea 7/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Osteogênese/genética , Osteoporose/genética , Fator 4 Ativador da Transcrição/genética , Adipócitos/metabolismo , Adipogenia/genética , Animais , Colágeno Tipo I/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Homeostase/genética , Humanos , Células-Tronco Mesenquimais , Camundongos , Camundongos Knockout , Osteoblastos/metabolismo , Osteoporose/patologia , Regiões Promotoras Genéticas/genética , RNA-Seq , Proteínas Repressoras/genética , Proteína Smad1/genética , Proteína 1 Relacionada a Twist/genética , Via de Sinalização Wnt/genética
8.
Nat Commun ; 12(1): 420, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462242

RESUMO

Adult stem cell identity, plasticity, and homeostasis are precisely orchestrated by lineage-restricted epigenetic and transcriptional regulatory networks. Here, by integrating super-enhancer and chromatin accessibility landscapes, we delineate core transcription regulatory circuitries (CRCs) of limbal stem/progenitor cells (LSCs) and find that RUNX1 and SMAD3 are required for maintenance of corneal epithelial identity and homeostasis. RUNX1 or SMAD3 depletion inhibits PAX6 and induces LSCs to differentiate into epidermal-like epithelial cells. RUNX1, PAX6, and SMAD3 (RPS) interact with each other and synergistically establish a CRC to govern the lineage-specific cis-regulatory atlas. Moreover, RUNX1 shapes LSC chromatin architecture via modulating H3K27ac deposition. Disturbance of RPS cooperation results in cell identity switching and dysfunction of the corneal epithelium, which is strongly linked to various human corneal diseases. Our work highlights CRC TF cooperativity for establishment of stem cell identity and lineage commitment, and provides comprehensive regulatory principles for human stratified epithelial homeostasis and pathogenesis.


Assuntos
Células-Tronco Adultas/metabolismo , Plasticidade Celular/genética , Doenças da Córnea/patologia , Epitélio Anterior/fisiologia , Redes Reguladoras de Genes/fisiologia , Adolescente , Adulto , Idoso , Linhagem da Célula/genética , Células Cultivadas , Criança , Cromatina/metabolismo , Sequenciamento de Cromatina por Imunoprecipitação , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Doenças da Córnea/genética , Epitélio Anterior/citologia , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Limbo da Córnea/citologia , Masculino , Pessoa de Meia-Idade , Fator de Transcrição PAX6/metabolismo , Cultura Primária de Células , RNA-Seq , Proteína Smad3/genética , Proteína Smad3/metabolismo
9.
Nat Commun ; 12(1): 520, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483506

RESUMO

The fusion oncogene RUNX1/RUNX1T1 encodes an aberrant transcription factor, which plays a key role in the initiation and maintenance of acute myeloid leukemia. Here we show that the RUNX1/RUNX1T1 oncogene is a regulator of alternative RNA splicing in leukemic cells. The comprehensive analysis of RUNX1/RUNX1T1-associated splicing events identifies two principal mechanisms that underlie the differential production of RNA isoforms: (i) RUNX1/RUNX1T1-mediated regulation of alternative transcription start site selection, and (ii) direct or indirect control of the expression of genes encoding splicing factors. The first mechanism leads to the expression of RNA isoforms with alternative structure of the 5'-UTR regions. The second mechanism generates alternative transcripts with new junctions between internal cassettes and constitutive exons. We also show that RUNX1/RUNX1T1-mediated differential splicing affects several functional groups of genes and produces proteins with unique conserved domain structures. In summary, this study reveals alternative splicing as an important component of transcriptome re-organization in leukemia by an aberrant transcriptional regulator.


Assuntos
Processamento Alternativo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Doença Aguda , Linhagem Celular Tumoral , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Perfilação da Expressão Gênica/métodos , Humanos , Leucemia Mieloide/patologia , Modelos Genéticos , Proteínas de Fusão Oncogênica/metabolismo , Interferência de RNA , Isoformas de RNA/genética , Isoformas de RNA/metabolismo , Proteína 1 Parceira de Translocação de RUNX1/metabolismo , Sítio de Iniciação de Transcrição
10.
Gene ; 764: 145099, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32861879

RESUMO

Down syndrome (DS, trisomy 21) is the most common major chromosomal aneuploidy compatible with life. The additional whole or partial copy of chromosome 21 results in genome-wide imbalances that drive the complex pathobiology of DS. Differential DNA methylation in the context of trisomy 21 may contribute to the variable architecture of the DS phenotype. The goal of this study was to examine the genomic DNA methylation landscape in myocardial tissue from non-fetal individuals with DS. >480,000 unique CpG sites were interrogated in myocardial DNA samples from individuals with (n = 12) and without DS (n = 12) using DNA methylation arrays. A total of 93 highly differentially methylated CpG sites and 16 differentially methylated regions were identified in myocardial DNA from subjects with DS. There were 18 differentially methylated CpG sites in chromosome 21, including 5 highly differentially methylated sites. A CpG site in the RUNX1 locus was differentially methylated in DS myocardium, and linear regression suggests that donors' age, gender, DS status, and RUNX1 methylation may contribute up to ~51% of the variability in RUNX1 mRNA expression. In DS myocardium, only 58% of the genes overlapping with differentially methylated regions codify for proteins with known functions and 24% are non-coding RNAs. This study provides an initial snapshot on the extent of genome-wide differential methylation in myocardial tissue from persons with DS.


Assuntos
Ilhas de CpG/genética , Metilação de DNA , Síndrome de Down/genética , Epigênese Genética , Miocárdio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Cromossomos Humanos Par 21/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Epigenômica , Feminino , Loci Gênicos/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Adulto Jovem
11.
Mol Cell ; 81(3): 530-545.e5, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33382982

RESUMO

Transcription factors regulate gene networks controlling normal hematopoiesis and are frequently deregulated in acute myeloid leukemia (AML). Critical to our understanding of the mechanism of cellular transformation by oncogenic transcription factors is the ability to define their direct gene targets. However, gene network cascades can change within minutes to hours, making it difficult to distinguish direct from secondary or compensatory transcriptional changes by traditional methodologies. To overcome this limitation, we devised cell models in which the AML1-ETO protein could be quickly degraded upon addition of a small molecule. The rapid kinetics of AML1-ETO removal, when combined with analysis of transcriptional output by nascent transcript analysis and genome-wide AML1-ETO binding by CUT&RUN, enabled the identification of direct gene targets that constitute a core AML1-ETO regulatory network. Moreover, derepression of this gene network was associated with RUNX1 DNA binding and triggered a transcription cascade ultimately resulting in myeloid differentiation.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , RNA Neoplásico/biossíntese , Proteína 1 Parceira de Translocação de RUNX1/metabolismo , Transcrição Genética , Acetilação , Sítios de Ligação , Ligação Competitiva , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Autorrenovação Celular , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Sangue Fetal/citologia , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes , Células HEK293 , Células-Tronco Hematopoéticas/patologia , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/patologia , Proteínas de Fusão Oncogênica/genética , Ligação Proteica , Proteólise , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Neoplásico/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Tempo , Transcriptoma
13.
Hematology ; 25(1): 494-501, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33317419

RESUMO

OBJECTIVES: RUNX1 mutations have been widely found in patients with myelodysplastic syndrome (MDS). Majority of reports revealed that RUNX1 mutations are associated with a poor prognosis. However, discrepancies still remain. The results of univariate analysis were not confirmed in multivariate analysis in some cases. Therefore, we performed a meta-analysis to assess the prognostic effect of RUNX1 mutations in MDS. METHODS: We extracted data from qualified studies that were searched from PubMed, Embase and the Cochrane Library. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for the overall survival (OS) and leukemia free survival (LFS) were pooled from the multivariate Cox proportional hazard models. RESULTS: Sixteen studies containing 5422 patients were included in this meta-analysis. There were 617 patients with mutated RUNX1 and 4805 patients with wide type RUNX1. The total HR for OS was 1.43 (95% CI = 1.21-1.70, P < 0.0001) and the counterpart of LFS was 1.88 (95% CI = 1.42-2.51, P < 0.0001). DISCUSSION AND CONCLUSION: These results suggest that the RUNX1 mutations are associated with unfavorable outcomes and shorter survival in patients with MDS. Furthermore, poor prognosis of patients might be alleviated by stem cell transplantation. Patients bearing these mutations should be prioritized for aggressive therapy.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Predisposição Genética para Doença , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Alelos , Terapia Combinada , Gerenciamento Clínico , Estudos de Associação Genética , Humanos , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/terapia , Prognóstico , Modelos de Riscos Proporcionais
14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1510-1515, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067946

RESUMO

OBJECTIVE: To investigate the clinical prognostic factors of initially-treated AML children with t(8;21)/RUNX1-RUNX1T1+. METHODS: Clinical data of 41 initially-treated AML children with t(8;21)/RUNX1-RUNX1T1+ in our hospital in period from January 2009 to January 2017 were retrospectively analyzed. The baseline clinical characteristics, cumulative recurrence, event-free survival (EFS) and overall survival (OS) were recorded, and the influencing factors of prognosis were evaluated by χ2 test and Cox regression model. RESULTS: The complete remission (CR) rates in the first course and the second course of induction chemotherapy were respectively 82.93% (34/41) and 97.56% (40/41). The median EFS time and OS time were 30 months and 31 months respectively. The EFS rate and OS rate of children with CR after the first treatment course were significantly higher than those of children without CR (P<0.05). The EFS rate of male children was significantly higher than that of female children (P<0.05). The OS rate of children < 10 years old was significantly higher than that of children≥10 years old (P<0.05). The expression level of RUNX1-RUNX1T1 gene after the second induction remission was the influencing factor of cumulative recurrence rate, EFS rate and OS rate in children (P<0.05). Multivariate analysis by Cox regression model showed that the decreased levels of RUNX1-RUNX1T1 gene expression < 3 log after the second induction remission was the independent risk factor for EFS rate and OS rate in children (P<0.05). The cumulative recurrence rate of children with RUNX1-RUNX1T1 gene expression increase for>1 log after decreased 3 log was significantly higher than that of children with≤1 log (P<0.05). CONCLUSION: Iuithally-treated AML children with t(8;21)/RUNX1-RUNX1T1+ show the fine clinical prognosis after standard chemotherapy. The expression level of RUNX1-RUNX1T1 gene should be closely relates with the recurrence and long-term survival of AML children.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Leucemia Mieloide Aguda , Criança , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Recidiva Local de Neoplasia , Prognóstico , Proteína 1 Parceira de Translocação de RUNX1 , Estudos Retrospectivos
15.
Medicine (Baltimore) ; 99(40): e22488, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019444

RESUMO

RATIONALE: Some acute myeloid leukemia (AML) patients present with features mimicking the classical hypergranular subtype of acute promyelocytic leukemia (APL) but without the typical promyelocytic leukemia/retinoic acid receptor α (PML/RARα) rearrangement. Herein, we report an AML patient resembling APL but with nucleoporin 98/retinoid acid receptor gamma gene (NUP98/RARG) fusion transcript and Runt-related transcription factor 1 (RUNX1) mutation. PATIENT CONCERNS: An 18-year-old male presented at the hospital with a diagnosis of AML. DIAGNOSES: The patient was diagnosed with bone marrow examination. Bone marrow smear displayed 90.5% promyelocytes. Fluorescence in situ hybridization analysis failed to detect the PML/RARα fusion transcript or RARα amplification. While real-time polymerase chain reaction showed positivity for the NUP98/RARG fusion transcript. G-banding karyotype analysis showed a normal karyotype. INTERVENTIONS: The patient showed resistance to arsenic trioxide and standard 3 + 7 chemotherapy, but eventually achieved complete remission through the Homoharringtonine, Cytarabine, and Aclarubicin chemotherapy. OUTCOMES: These measures resulted in a rapid response and disease control. LESSONS: Acute myeloid leukemia with the NUP98/RARG fusion gene and the RUNX1 mutation may be a special subtype of AML and may benefit from the alkaloid-based regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Adolescente , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Diagnóstico Diferencial , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Promielocítica Aguda/diagnóstico , Masculino , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Receptores do Ácido Retinoico/genética
16.
Proc Natl Acad Sci U S A ; 117(38): 23626-23635, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32883883

RESUMO

Hematopoietic stem and progenitor cell (HSPC) formation and lineage differentiation involve gene expression programs orchestrated by transcription factors and epigenetic regulators. Genetic disruption of the chromatin remodeler chromodomain-helicase-DNA-binding protein 7 (CHD7) expanded phenotypic HSPCs, erythroid, and myeloid lineages in zebrafish and mouse embryos. CHD7 acts to suppress hematopoietic differentiation. Binding motifs for RUNX and other hematopoietic transcription factors are enriched at sites occupied by CHD7, and decreased RUNX1 occupancy correlated with loss of CHD7 localization. CHD7 physically interacts with RUNX1 and suppresses RUNX1-induced expansion of HSPCs during development through modulation of RUNX1 activity. Consequently, the RUNX1:CHD7 axis provides proper timing and function of HSPCs as they emerge during hematopoietic development or mature in adults, representing a distinct and evolutionarily conserved control mechanism to ensure accurate hematopoietic lineage differentiation.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Proteínas de Ligação a DNA , Hematopoese , Animais , Diferenciação Celular , Linhagem Celular , Subunidade alfa 2 de Fator de Ligação ao Core/química , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Células-Tronco Hematopoéticas , Humanos , Masculino , Camundongos , Baço/citologia , Peixe-Zebra
17.
Ann Hematol ; 99(10): 2329-2338, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32821971

RESUMO

Patients with the pre-leukemia bone marrow failure syndrome called severe congenital neutropenia (CN) have an approximately 15% risk of developing acute myeloid leukemia (AML; called here CN/AML). Most CN/AML patients co-acquire CSF3R and RUNX1 mutations, which play cooperative roles in the development of AML. To establish an in vitro model of leukemogenesis, we utilized bone marrow lin- cells from transgenic C57BL/6-d715 Csf3r mice expressing a CN patient-mimicking truncated CSF3R mutation. We transduced these cells with vectors encoding RUNX1 wild type (WT) or RUNX1 mutant proteins carrying the R139G or R174L mutations. Cells transduced with these RUNX1 mutants showed diminished in vitro myeloid differentiation and elevated replating capacity, compared with those expressing WT RUNX1. mRNA expression analysis showed that cells transduced with the RUNX1 mutants exhibited hyperactivation of inflammatory signaling and innate immunity pathways, including IL-6, TLR, NF-kappaB, IFN, and TREM1 signaling. These data suggest that the expression of mutated RUNX1 in a CSF3R-mutated background may activate the pro-inflammatory cell state and inhibit myeloid differentiation.


Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Células-Tronco Hematopoéticas/patologia , Células Mieloides/patologia , Mielopoese/genética , Neutropenia/congênito , Pré-Leucemia/genética , Receptores de Fator Estimulador de Colônias/genética , Animais , Divisão Celular , Ensaio de Unidades Formadoras de Colônias , Síndrome Congênita de Insuficiência da Medula Óssea/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Perfilação da Expressão Gênica , Imunidade Inata , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neutropenia/genética , Neutropenia/patologia , Pré-Leucemia/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Fator Estimulador de Colônias/fisiologia , Proteínas Recombinantes/genética , Organismos Livres de Patógenos Específicos
18.
Rinsho Ketsueki ; 61(6): 687-696, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32624544

RESUMO

The RUNX1 gene is a critical transcription factor for the generation and maintenance of hematopoietic stem cells. RUNX1 is also one of the most frequently mutated gene in sporadic leukemias. Heterozygous loss-of-function mutations of the RUNX1 gene in the germline cause a rare autosomal dominant disorder called familial platelet disorder with propensity to acute myelogenous leukemia (FPD/AML). Besides the preexisting platelet disorder in FPD/AML patients, AML also develops in 20-60% of affected individuals. Since its discovery by the Gilliland group in 1999, RUNX1 mutation in the germline has been extensively investigated in the field. The past two decades of research have taught us three important lessons: 1) patients with FPD/AML display atypical symptoms and they have a widened clinical spectrum of FPD, such as eczema and syndromic thrombocytopenia, 2) the elucidation of variant of uncertain significance (VUS) of RUNX1 have revealed their role in epigenetic functions and involvement in the Fanconi anemia DNA repair pathway, and 3) non-coding mutations of RUNX1 also causes FPD/AML. In three distinct familial cases, an enhancer for RUNX1, eR1, was either lost or disconnected from the promoter through genetic deletion or chromosomal translocation abnormalities. This experience, with congenital mutations of RUNX1, will be very useful for future research for a series of other leukemia-causing germline mutations that have been recently identified.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Linhagem
19.
Hum Genet ; 139(12): 1555-1563, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32535809

RESUMO

The chromosomal region critical in Down syndrome has long been analyzed through genotype-phenotype correlation studies using data from many patients with partial trisomy 21. Owing to that, a relatively small region of human chromosome 21 (35.9 ~ 38.0 Mb) has been considered as Down syndrome critical region (DSCR). In this study, microarray-based comparative genomic hybridization analysis identified complex rearrangements of chromosome 21 in a patient manifesting clinical features partially overlapped with that of Down syndrome. Although the patient did not show up-slanting palpebral fissures and single transverse palmar creases, other symptoms were consistent with Down syndrome. Rearrangements were analyzed by whole-genome sequencing using Nanopore long-read sequencing. The analysis revealed that chromosome 21 was fragmented into seven segments and reassembled by six connected points. Among 12 breakpoints, 5 are located within the short region and overlapped with repeated segments. The rearrangement resulted in a maximum gain of five copies, but no region showed loss of genomic copy numbers. Breakpoint-junctions showed no homologous region. Based on these findings, chromoanasynthesis was considered as the mechanism. Although the distal 21q22.13 region was not included in the aberrant regions, some of the genes located on the duplicated regions, SOD1, SON, ITSN1, RCAN1, and RUNX1, were considered as possible candidate genes for clinical features of the patient. We discussed the critical region for Down syndrome, with the literature review.


Assuntos
Cromossomos Humanos Par 21/genética , Cromossomos Humanos/genética , Síndrome de Down/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Aberrações Cromossômicas , Hibridização Genômica Comparativa/métodos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas de Ligação a DNA/genética , Síndrome de Down/fisiopatologia , Feminino , Dosagem de Genes/genética , Estudos de Associação Genética , Humanos , Hibridização in Situ Fluorescente/métodos , Lactente , Análise em Microsséries/métodos , Antígenos de Histocompatibilidade Menor/genética , Proteínas Musculares/genética , Superóxido Dismutase-1/genética , Sequenciamento Completo do Genoma
20.
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
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