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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 450-455, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33812414

RESUMO

OBJECTIVE: To investigate the relationship between acute myeloid leukemia (AML) patients ASXL2, ZBTB7A gene mutations and the prognosis. METHODS: 42 AML Patients treated in our hospital from January 2014 to January 2016 were selected and ASXL2 and ZBTB7A genes of their bone marrow samples were sequenced, the genetic characteristics and prognosis of core-binding factor-AML(CBF-AML) patients with ASXL2 and ZBTB7A mutations were analyzed. RESULTS: ASXL2 (33.3%) and ZBTB7A (9.5%) mutations were found in t (8; 21) AML patients. Compared with wild-type, patients with ASXL2 mutations showed significantly higher white blood cell count at diagnosis ï¼»(9.49±1.85)×109/L vs (8.3±1.14)×109/L,P=0.03ï¼½ and lower frequency of sex chromosome deletions (21.43% vs 71.43%, P=0.02), respectively. ASXL2 mutation showed mutually exclusive with ASXL1 mutation (P=0.035). The proportion of chromatin modifier gene ATRX and BCOR mutations was higher in patients with ASXL2 mutation (P=0.032, P=0.005).ASXL2 and ZBTB7A mutations showed no significant effect to overall survival or event-free survival rate in patients with AML. CONCLUSION: ASXL2 and ZBTB7A mutations are frequently found in t (8; 21) AML patients. The mutation of ASXL2 and ZBTB7A genes shows no significant effect on the prognosis of AML patients.


Assuntos
Proteínas de Ligação a DNA , Leucemia Mieloide Aguda , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Proteínas de Fusão Oncogênica/genética , Prognóstico , Proteínas Repressoras/genética , Fatores de Transcrição/genética
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 369-373, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33812401

RESUMO

OBJECTIVE: To analyze the prognostic factors of AML children with CBFß/MYH11 positive. METHODS: Twenty-eight children with CBFß/MYH11 positive treated in our hospital from May 2012 to June 2018 were selected, the clinical data and curative were analyzed and evaluated. RESULTS: Five-year OS and 5-year EFS rate of CBFß/MYH11 positive AML children was 76.8% and 64.0% efficacy, respectively. Univariate analysis results showed that the OS rate of CBFß/MYH11 positive AML children with WBC<60.0×109/L was 86.5%, which was significantly higher than those of CBFß/MYH11 positive AML children with WBC≥60.0×109/L (χ2=3.891, P<0.05). The EFS rate of CBFß/MYH11 positive AML children with WBC<60.0×109/L was 76.0%, which was significantly higher than those of AML children with WBC≥60.0×109/L (χ2=4.588, P<0.05). The EFS rate of CBFß/MYH11 positive AML children with XRCC-Thr241Met wild type was 77.9%, which was significantly higher than those of AML children with XRCC-Thr241Met variant (χ2=3.960, P<0.05). Cox multivariate survival analysis results showed that WBC level at initial diagnosis was the risk factor for OS rate. The WBC level and XRCC-Thr241Met type at initial diagnosis were the risk factors for EFS rate. CONCLUSION: WBC level and XRCC-Thr241Met genotype at initial diagnosis are the major affecting factors for prognosis of AML children with CBFß/MYH11 positive.


Assuntos
Inversão Cromossômica , Leucemia Mieloide Aguda , Criança , Genótipo , Humanos , Leucemia Mieloide Aguda/genética , Cadeias Pesadas de Miosina , Proteínas de Fusão Oncogênica , Prognóstico
3.
Nat Commun ; 12(1): 1491, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674598

RESUMO

Abnormally formed FUS/EWS/TAF15 (FET) fusion oncoproteins are essential oncogenic drivers in many human cancers. Interestingly, at the molecular level, they also form biomolecular condensates at specific loci. However, how these condensates lead to gene transcription and how features encoded in the DNA element regulate condensate formation remain unclear. Here, we develop an in vitro single-molecule assay to visualize phase separation on DNA. Using this technique, we observe that FET fusion proteins undergo phase separation at target binding loci and the phase separated condensates recruit RNA polymerase II and enhance gene transcription. Furthermore, we determine a threshold number of fusion-binding DNA elements that can enhance the formation of FET fusion protein condensates. These findings suggest that FET fusion oncoprotein promotes aberrant gene transcription through loci-specific phase separation, which may contribute to their oncogenic transformation ability in relevant cancers, such as sarcomas and leukemia.


Assuntos
Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fatores Associados à Proteína de Ligação a TATA/genética , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Transcrição Genética , DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , RNA Polimerase II/metabolismo , Proteína EWS de Ligação a RNA , Proteína FUS de Ligação a RNA
4.
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
5.
Medicine (Baltimore) ; 100(8): e24802, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663097

RESUMO

RATIONALE: Clitoris swelling as the initial clinical presentation of acute lymphoblastic leukemia (ALL) is extremely rare. These patients may be misdiagnosed with acute myeloid leukemia or solid tumor, and the main treatment can also be delayed. PATIENT CONCERNS: A 2.10-year-old girl was referred to the pediatric surgery clinic with a worsening onset of clitoris swellings. The patient was afebrile and well appearing. Multiple retroperitoneal mass were confirmed by computed tomography (CT) and high serum neuron-specific enolase level was high. She was scheduled for an abdominal biopsy from the retroperitoneal mass suspicious of neuroblastoma. DIAGNOSES: The child was eventually diagnosed as having precursor B cell ALL with central nervous system involved, with TCF3-PBX1 fusion gene and additional chromosomal aberrations, based on examinations of the bone marrow and brain magnetic resonance imaging. INTERVENTIONS: Before the diagnosis of leukemia, the patient was given symptomatic treatment for 1 week. She was treated with chemotherapy in accordance with the Chinese Children's Cancer Group protocol 2015 after confirmed diagnosis. OUTCOMES: After induction chemotherapy for ALL, although the girl had transiently clinical remission, the bone marrow aspirate indicated a poor outcome. Our patient discontinued treatment and discharged. From literature review, there was only 1 case of in acute myeloid leukemia with clitoris swelling as the initial symptom. LESSONS: The clinical symptoms of ALL with clitoris swelling are not typical, with a high rate of misdiagnosis. When the cause of clitoris swelling is unknown, ALL should be considered. Bone marrow aspiration must be done before doing a more invasive investigation like biopsy.


Assuntos
Clitóris/patologia , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Pré-Escolar , Feminino , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico
7.
Nat Commun ; 12(1): 1045, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594072

RESUMO

Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-'reading' bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.


Assuntos
Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/química , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Correpressoras/química , Proteínas Correpressoras/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Leucemia Mieloide Aguda/patologia , Lisina Acetiltransferase 5/metabolismo , Acetilação , Animais , Carcinogênese , Diferenciação Celular , Proliferação de Células , Transformação Celular Neoplásica , Modelos Animais de Doenças , Elementos Facilitadores Genéticos/genética , Regulação Leucêmica da Expressão Gênica , Genoma Humano , Células HEK293 , Células-Tronco Hematopoéticas/metabolismo , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Camundongos Endogâmicos BALB C , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas de Fusão Oncogênica/metabolismo , Ligação Proteica , Domínios Proteicos , Fatores de Transcrição/metabolismo
8.
Medicine (Baltimore) ; 100(4): e24463, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33530256

RESUMO

INTRODUCTION: Standardized systemic treatment options are lacking for carcinoma ex pleomorphic adenoma, which is a rare and aggressive tumor primarily found in salivary glands.Here we report the case of a 63-year-old male with carcinoma ex pleomorphic adenoma of the left parotid and parapharyngeal space harboring a neurotrophic receptor tyrosine kinase (NTRK) 2 fusion who was treated with a small molecule inhibitor that targets the tropomyosin receptor kinase (TRK) proteins. To the best of our knowledge, no similar case has been described in the literature so far. PATIENT CONCERNS: After multiple surgical resections and radiotherapy for localized cancer disease over several years, our patient again developed an increasing swelling and pain around the left ear and numbness of the left half of the face. DIAGNOSIS: Magnetic resonance imaging and positron emission tomography/computed tomography scans showed tumor recurrence in the left parotid, below the left ear, and in the parapharyngeal space, as well as metastases of the lungs and cervical lymph nodes. As data on the efficacy of systemic therapies for inoperable carcinoma ex pleomorphic adenoma are scarce, we performed a next-generation sequencing that revealed the presence of a hitherto unknown NTRK2 fusion. INTERVENTIONS: Treatment with the TRK inhibitor larotrectinib was initiated, which induced rapid symptom improvement. However, part of the tumor had to be removed shortly afterwards due to local progression. Molecular testing did not demonstrate any alterations accounting for resistance to larotrectinib, with maintenance of the NTRK2 fusion. OUTCOMES: Three months later, imaging confirmed mixed response. While the reason for this remains unknown, the patient is in good condition and continues to receive larotrectinib. CONCLUSION: It remains unclear why our patient showed mixed response to larotrectinib and further studies are needed to explore other possible mechanisms of resistance.


Assuntos
Adenoma Pleomorfo/tratamento farmacológico , Neoplasias Parotídeas/tratamento farmacológico , Neoplasias Faríngeas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenoma Pleomorfo/genética , Adenoma Pleomorfo/cirurgia , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Glicoproteínas de Membrana , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Proteínas de Fusão Oncogênica/genética , Neoplasias Parotídeas/genética , Neoplasias Parotídeas/cirurgia , Neoplasias Faríngeas/genética , Neoplasias Faríngeas/patologia , Receptor trkB
9.
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
11.
Nat Struct Mol Biol ; 28(2): 190-201, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33479542

RESUMO

NUP98 fusion proteins cause leukemia via unknown molecular mechanisms. All NUP98 fusion proteins share an intrinsically disordered region (IDR) in the NUP98 N terminus, featuring repeats of phenylalanine-glycine (FG), and C-terminal fusion partners often function in gene control. We investigated whether mechanisms of oncogenic transformation by NUP98 fusion proteins are hardwired in their protein interactomes. Affinity purification coupled to mass spectrometry (MS) and confocal imaging of five NUP98 fusion proteins expressed in human leukemia cells revealed that shared interactors were enriched for proteins involved in biomolecular condensation and that they colocalized with NUP98 fusion proteins in nuclear puncta. We developed biotinylated isoxazole-mediated condensome MS (biCon-MS) to show that NUP98 fusion proteins alter the global composition of biomolecular condensates. An artificial FG-repeat-containing fusion protein phenocopied the nuclear localization patterns of NUP98 fusion proteins and their capability to drive oncogenic gene expression programs. Thus, we propose that IDR-containing fusion proteins combine biomolecular condensation with transcriptional control to induce cancer.


Assuntos
Núcleo Celular/metabolismo , Proteínas de Homeodomínio , Leucemia , Complexo de Proteínas Formadoras de Poros Nucleares , Proteínas de Fusão Oncogênica , Animais , Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Células HEK293 , Células HL-60 , Proteínas de Homeodomínio/química , Proteínas de Homeodomínio/fisiologia , Humanos , Leucemia/metabolismo , Leucemia/patologia , Camundongos , Células NIH 3T3 , Complexo de Proteínas Formadoras de Poros Nucleares/química , Complexo de Proteínas Formadoras de Poros Nucleares/fisiologia , Proteínas de Fusão Oncogênica/química , Proteínas de Fusão Oncogênica/fisiologia
12.
Mol Carcinog ; 60(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33428799

RESUMO

Acute promyelocytic leukemia (APL) is a unique disease entity in acute myeloid leukemia, characterized by PML-RARA fusion gene, which is generated by chromosomal translocation t(15;17)(q24;q21). We identified TNRC18-RARA as novel RARA fusion in resembling APL. Our study highlights the importance of combining multiple molecular techniques to characterize and optimally manage APL lacking classic t(15;17)(q24;q12)/PML-RARA fusion.


Assuntos
Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 17/genética , Leucemia Promielocítica Aguda/genética , Proteínas de Fusão Oncogênica/genética , Receptor alfa de Ácido Retinoico/genética , Translocação Genética , Regulação Leucêmica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/metabolismo , Receptor alfa de Ácido Retinoico/metabolismo
14.
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
15.
BMJ Case Rep ; 14(1)2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33495184

RESUMO

A 70-year-old man with medical history of IgG kappa multiple myeloma, initially diagnosed in 2017, underwent induction therapy with carfilzomib, lenalidomide and dexamethasone followed by autologous haematopoietic stem cell transplantation. Nine months following transplant, disease relapsed in the form of plasma cell leukaemia. Fluorescent in situ hybridisation of malignant plasma cells revealed t(11;14). A combination therapy including venetoclax was used based on efficacy data for Bcl-2 inhibitor venetoclax from available early-phase clinical trials in patients with relapsed multiple myeloma with t(11;14) and other published case studies. Unfortunately, the disease was primary refractory, and after further ineffective therapies, the patient did not have a successful outcome.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Leucemia Plasmocitária/tratamento farmacológico , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia/tratamento farmacológico , Sulfonamidas/uso terapêutico , Idoso , Dexametasona/administração & dosagem , Humanos , Hibridização in Situ Fluorescente , Lenalidomida/administração & dosagem , Leucemia Plasmocitária/diagnóstico por imagem , Leucemia Plasmocitária/genética , Leucemia Plasmocitária/patologia , Masculino , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Oligopeptídeos/administração & dosagem , Proteínas de Fusão Oncogênica , Translocação Genética , Transplante Autólogo , Falha de Tratamento
16.
BMJ Case Rep ; 14(1)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33509883
17.
Nat Med ; 27(2): 289-300, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33495604

RESUMO

Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and is characterized by low T cell infiltration. Here, we studied the cancer-immune interplay in SyS using an integrative approach that combines single-cell RNA sequencing (scRNA-seq), spatial profiling and genetic and pharmacological perturbations. scRNA-seq of 16,872 cells from 12 human SyS tumors uncovered a malignant subpopulation that marks immune-deprived niches in situ and is predictive of poor clinical outcomes in two independent cohorts. Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. This drug combination enhanced malignant-cell immunogenicity in SyS models, leading to induced T cell reactivity and T cell-mediated killing. Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.


Assuntos
Carcinogênese/genética , Terapia de Alvo Molecular , Proteínas de Fusão Oncogênica/genética , Sarcoma Sinovial/tratamento farmacológico , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/genética , Histona Desacetilases/uso terapêutico , Humanos , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Oncogenes/genética , RNA-Seq , Sarcoma Sinovial/genética , Sarcoma Sinovial/patologia , Análise de Célula Única
18.
Nat Commun ; 12(1): 192, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420019

RESUMO

Rhabdomyosarcoma (RMS) is an aggressive pediatric malignancy of the muscle, that includes Fusion Positive (FP)-RMS harboring PAX3/7-FOXO1 and Fusion Negative (FN)-RMS commonly with RAS pathway mutations. RMS express myogenic master transcription factors MYOD and MYOG yet are unable to terminally differentiate. Here, we report that SNAI2 is highly expressed in FN-RMS, is oncogenic, blocks myogenic differentiation, and promotes growth. MYOD activates SNAI2 transcription via super enhancers with striped 3D contact architecture. Genome wide chromatin binding analysis demonstrates that SNAI2 preferentially binds enhancer elements and competes with MYOD at a subset of myogenic enhancers required for terminal differentiation. SNAI2 also suppresses expression of a muscle differentiation program modulated by MYOG, MEF2, and CDKN1A. Further, RAS/MEK-signaling modulates SNAI2 levels and binding to chromatin, suggesting that the differentiation blockade by oncogenic RAS is mediated in part by SNAI2. Thus, an interplay between SNAI2, MYOD, and RAS prevents myogenic differentiation and promotes tumorigenesis.


Assuntos
Carcinogênese/metabolismo , Diferenciação Celular , Proteína MyoD/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Rabdomiossarcoma/genética , Rabdomiossarcoma/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Animais , Carcinogênese/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Fatores de Transcrição MEF2/metabolismo , Masculino , Camundongos , Camundongos SCID , Desenvolvimento Muscular/genética , Proteína MyoD/genética , Miogenina/metabolismo , Proteínas de Fusão Oncogênica/genética , Oncogenes , Rabdomiossarcoma/patologia , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Embrionário/genética , Fatores de Transcrição da Família Snail/genética , Transcriptoma
19.
Methods Mol Biol ; 2226: 3-14, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33326089

RESUMO

Ewing sarcoma (EwS) is a rare bone or soft tissue tumor that occurs early in life and as such genetic variation is a major contributor to EwS risk. To date, genetic investigations have identified key somatic mutations and germline variants of importance for EwS risk. While substantial progress is being made in uncovering the genetic etiology of EwS, considerable gaps in knowledge remain. Herein, we provide a summary of methodological approaches for future genomic investigations of EwS. We anticipate this recommended analytical framework for germline and somatic investigations, along with genomic data from growing EwS case series, will aid in accelerating new genomic discoveries in EwS and expand knowledge of the genetic architecture of EwS.


Assuntos
Biomarcadores Tumorais , Neoplasias Ósseas/genética , Predisposição Genética para Doença , Variação Genética , Mutação em Linhagem Germinativa , Sarcoma de Ewing/genética , Animais , Neoplasias Ósseas/diagnóstico , Estudos de Associação Genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Proteínas de Fusão Oncogênica/genética , Sarcoma de Ewing/diagnóstico
20.
Methods Mol Biol ; 2226: 85-103, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33326095

RESUMO

Ewing sarcoma is a rare and aggressive tumor that affects children and young adults. Ewing sarcomas are characterized by specific chromosomal translocations that give rise to fusion transcripts that codify for aberrant transcription factors. More than 95% of Ewing sarcoma harbor translocations that produce the fusion of the EWSR1 gene with the transcription factors FLI1 or ERG. This feature can be used to diagnose this entity unambiguously.In this chapter we describe a RT-PCR method that allows for the detection of the most frequent alterations with elevated specificity and sensitivity which is able to distinguish among the different types of fusions. The method is fast and economical, and can be carried out with the conventional equipment available in any molecular biology laboratory.


Assuntos
Biomarcadores Tumorais , Neoplasias Ósseas/diagnóstico , Técnicas de Diagnóstico Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoma de Ewing/diagnóstico , Neoplasias Ósseas/genética , Loci Gênicos , Humanos , Proteínas de Fusão Oncogênica/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Sarcoma de Ewing/genética , Translocação Genética
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