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2.
Gene ; 726: 144154, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31589962

RESUMO

In this work the complete chloroplast DNAs of Allium paradoxum and Allium ursinum, two edible species of Allium subg. Amerallium (the first lineage), were sequenced, assembled, annotated, and compared with complete Allium plastomes of the second and third evolutionary lines from GenBank database. The A. ursinum plastome contains 90 predicted genes (81 unique) including 5 pseudogenes, while A. paradoxum has 88 predicted genes (79 unique) including 19 pseudogenes. The comparative analysis has revealed that the A. paradoxum plastome differs markedly from those of other species. Due to many deletions, the A. paradoxum plastome is the shortest of known for Allium species, being only 145,819 bp long. The most prominent distinctions are (1) a 4825 bp long local inversion that spans from the ndhE to the rpl32 gene in the small single copy region and (2) pseudogenization, or the loss of all NADH-genes. In contrast, the plastome of A. ursinum - a species from the first evolutionary line (as well as A. paradoxum) - resembles the Allium species of the second and third evolutionary lines, showing no large rearrangements or discrepancies in gene content. It is unclear yet whether only A. paradoxum was affected by some evolutionary events or its close relatives from both sect. Briseis and other sections of Amerallium were altered as well. We speculate the sunlight-intolerant, shade-loving nature of A. paradoxum and the impairment of the ndh genes in its plastome could be interrelated phenomena.


Assuntos
Allium/genética , Rearranjo Gênico/genética , Genes de Plantas/genética , Cebolas/genética , DNA de Cloroplastos/genética , DNA de Plantas/genética , Evolução Molecular , Genoma de Cloroplastos/genética , Genoma de Planta/genética , Filogenia , Folhas de Planta/genética , Pseudogenes/genética , Análise de Sequência de DNA/métodos
3.
Zhonghua Bing Li Xue Za Zhi ; 48(12): 928-933, 2019 Dec 08.
Artigo em Chinês | MEDLINE | ID: mdl-31818065

RESUMO

Objective: To study the clinicopathological characteristics of lung salivary gland-type tumors (SGT), and to compare with the corresponding primary SGT in salivary glands. Methods: Twenty-three cases of lung SGT were retrieved from the files of Peking University First Hospital from January 2004 to September 2018. The morphology, immunophenotype, genotype and outcome of these cases were analyzed. Results: The 23 patients included 13 males and 10 females, with age range of 13-79 years (median 54 years). There were 11 cases of adenoid cystic carcinoma, 10 cases of mucoepidermoid carcinoma (MEC), one case each of clear cell carcinoma and myoepithelioma. The morphology and immunophenotype of lung SGT were very similar to their counterparts in salivary gland. MYB rearrangement was detected in one of 11 adenoid cystic carcinomas. MAML2 rearrangement was detected in all the MECs. EWSR1 rearrangement was detected in the one case of clear cell carcinoma. Of patients with adenoid cystic carcinoma, the survival time was more than 60 months (three cases), 52 months (one case), and 12-36 months (three cases). There was no recurrence and death in seven cases of MEC with follow-up results. One case of clear cell carcinoma recurred after 52 months of follow-up. Conclusions: Although the SGT of lung and their counterparts in salivary gland are very similar in their morphology, immunophenotype, genotype and prognosis, there are also some differences between each other. MYB rearrangement can be detected in most adenoid cystic carcinomas of salivary gland, but rarely in lung adenoid cystic carcinoma. The prognosis of patients with lung MEC is better than that of patients with salivary gland MEC, while the prognosis of patients with lung adenoid cystic carcinoma is worse than that of patients with salivary gland adenoid cystic carcinoma.


Assuntos
Carcinoma Adenoide Cístico/patologia , Carcinoma Mucoepidermoide/patologia , Neoplasias Pulmonares/patologia , Neoplasias das Glândulas Salivares/patologia , Adolescente , Adulto , Idoso , Biomarcadores Tumorais , Feminino , Rearranjo Gênico , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Glândulas Salivares/patologia , Adulto Jovem
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1077-1080, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703129

RESUMO

OBJECTIVE: To assess the value of detecting multiple rearrangements of MLL gene in children with acute mononuclear leukemia (AML). METHODS: Eighty six children with AML were analyzed by fluorescence in situ hybridization (FISH), chromosomal karyotyping and multiplex reverse transcription-PCR (RT-PCR). RESULTS: Cross signals were detected by FISH in 26 cases, and 30.2% were detected with MLL gene rearrangements. R-band karyotyping analysis revealed 14 translocations with breakages involving 11q23 and 5 other aberrations, which yielded an overall detection rate of 22.1%. Multiple RT-PCR has detected 12 fusion genes produced by the MLL translocation, which yielded a detection rate of 14.0%. A significant difference was found in the detection rate of the three methods (P< 0.05). CONCLUSION: Combined use of FISH, chromosomal karyotyping and multiplex RT-PCR can improve the detection of MLL gene rearrangements and provide important clues for clinical diagnosis, treatment and prognosis of AML.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Criança , Cromossomos Humanos Par 11 , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Translocação Genética
6.
Rinsho Ketsueki ; 60(9): 1317-1323, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597858

RESUMO

Acute lymphoblastic leukemia (ALL) in infants under 1 is a rare and dismal disease. It is associated with a unique and specific biology, and 80% of cases harbor a KMT2A (MLL) gene rearrangement (KMT2A-r). In contrast to ALL in older children, with a survival rate of 80% or more, the prognosis of infant ALL is very poor, at 40%. In addition, the unique pharmacodynamics exhibited by infants has historically led to independent therapeutic development either in the U.S., Europe, or Japan. To improve the prognosis of infant ALL, it is necessary to uncover a supplementary novel effective agent to be used in combination with the existing conventional multi-agent chemotherapy. Because of the rarity of the disease, this could be only established by an international study, for which the consensus has already been established through discussions between the U.S., Europe, and Japan. Additionally, severe late effects in survivors are also problematic. Establishing novel treatment strategies to reduce relapse rates, treatment-related toxicities, and critical late effects is strongly encouraged in near future.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Europa (Continente) , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/genética , Humanos , Lactente , Japão , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Taxa de Sobrevida , Estados Unidos
7.
Ann Hematol ; 98(11): 2561-2567, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31515574

RESUMO

Overt central nervous system (CNS) involvement in aggressive non-Hodgkin's lymphoma (NHL) is rare at diagnosis. Much effort is put to identify risk factors for occult CNS involvement, and the risk assessment of CNS relapse. Prophylactic treatment carries risk of adverse events and its efficacy is not clear. Detection of cerebrospinal fluid molecular gene rearrangement (GRR) as a method to detect occult disease has been studied in acute leukemia and primary CNS lymphoma. To date, the capacity of a positive GRR in newly diagnosed NHL patients to predict CNS relapse has not been addressed. We retrospectively studied the prognostic value of GRR in cerebrospinal fluid samples of 148 newly diagnosed patients with high grade NHL. We demonstrate that positive GRR at diagnosis does not affect PFS or OS and did not predict CNS relapse. However, although numbers were small, repeated positive samples (≥ 2) correlated with a higher risk for CNS relapse (p = 0.048), possibly stressing the need for an aggressive preventive approach.


Assuntos
Neoplasias do Sistema Nervoso Central , Rearranjo Gênico , Linfoma não Hodgkin , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Feminino , Humanos , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
8.
Nucleic Acids Res ; 47(18): 9741-9760, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31504770

RESUMO

Extrachromosomal circular DNA (eccDNA) is both a driver of eukaryotic genome instability and a product of programmed genome rearrangements, but its extent had not been surveyed in Oxytricha, a ciliate with elaborate DNA elimination and translocation during development. Here, we captured rearrangement-specific circular DNA molecules across the genome to gain insight into its processes of programmed genome rearrangement. We recovered thousands of circularly excised Tc1/mariner-type transposable elements and high confidence non-repetitive germline-limited loci. We verified their bona fide circular topology using circular DNA deep-sequencing, 2D gel electrophoresis and inverse polymerase chain reaction. In contrast to the precise circular excision of transposable elements, we report widespread heterogeneity in the circular excision of non-repetitive germline-limited loci. We also demonstrate that circular DNAs are transcribed in Oxytricha, producing rearrangement-specific long non-coding RNAs. The programmed formation of thousands of eccDNA molecules makes Oxytricha a model system for studying nucleic acid topology. It also suggests involvement of eccDNA in programmed genome rearrangement.


Assuntos
DNA Circular/genética , Rearranjo Gênico/genética , Oxytricha/genética , Recombinação Genética , Citoplasma/genética , Elementos de DNA Transponíveis/genética , DNA de Protozoário/genética , Células Eucarióticas , Genoma de Protozoário/genética , Sequenciamento de Nucleotídeos em Larga Escala
9.
Int J Mol Sci ; 20(16)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412611

RESUMO

In 2011, the Vysis Break Apart ALK fluorescence in situ hybridization (FISH) assay was approved by the United States Food and Drug Administration as a companion diagnostic for detecting ALK rearrangement in lung cancer patients who may benefit from treatment of tyrosine kinase inhibitor therapy. This assay is the current "gold standard". According to updated ALK testing guidelines from the College of American Pathologists, the International Association for the Study of Lung Cancer and the Association for Molecular Pathology published in 2018, ALK immunohistochemistry is formally an alternative to ALK FISH, and simultaneous detection of multiple hot spots, including, at least, ALK, ROS1, RET, MET, ERBB2, BRAF and KRAS genes is also recommended while performing next generation sequencing (NGS)-based testing. Therefore, ALK status in a specimen can be tested by different methods and platforms, even in the same institution or laboratory. In this review, we discuss several clinically relevant technical aspects of ALK FISH, including pros and cons of the unique two-step (50- to 100-cell) analysis approach employed in the Vysis Break Apart ALK FISH assay, including: the preset cutoff value of ≥15% for a positive result; technical aspects and biology of discordant results obtained by different methods; and incidental findings, such as ALK copy number gain or amplification and co-existent driver mutations. These issues have practical implications for ALK testing in the clinical laboratory following the updated guidelines.


Assuntos
Quinase do Linfoma Anaplásico/genética , Rearranjo Gênico , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Algoritmos , Quinase do Linfoma Anaplásico/metabolismo , Biomarcadores Tumorais , Amplificação de Genes , Dosagem de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Mutação
10.
Int J Mol Sci ; 20(17)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466297

RESUMO

Phylogenetic framework for the closely related Ancylodiscoidinae and Ancyrocephalinae subfamilies remains contentious. As this issue was never studied using a large molecular marker, we sequenced the first two Ancylodiscoidinae mitogenomes: Thaparocleidus asoti and Thaparocleidus varicus. Both mitogenomes had two non-coding regions (NCRs) that contained a number of repetitive hairpin-forming elements (RHE). Due to these, the mitogenome of T. asoti (16,074 bp) is the longest among the Monogenea; especially large is its major NCR, with 3500 bp, approximately 1500 bp of which could not be sequenced (thus, the total mitogenome size is ≈ 17,600 bp). Although RHEs have been identified in other monopisthocotyleans, they appear to be independently derived in different taxa. The presence of RHEs may have contributed to the high gene order rearrangement rate observed in the two mitogenomes, including the first report of a transposition of rRNA genes within the Neodermata. Phylogenetic analyses using mitogenomic dataset produced Dactylogyrinae embedded within the Ancyrocephalinae (paraphyly), whereas Ancylodiscoidinae formed a sister-group with them. This was also supported by the gene order analysis. 28S rDNA dataset produced polyphyletic Dactylogyridae and Ancyrocephalinae. The phylogeny of the two subfamilies shall have to be further evaluated with more data.


Assuntos
Genoma Helmíntico , Genoma Mitocondrial , Platelmintos/genética , RNA Ribossômico/genética , Animais , Evolução Molecular , Rearranjo Gênico , Sequências Repetidas Invertidas , Filogenia , Platelmintos/classificação , RNA Ribossômico/química
11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 777-780, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400126

RESUMO

OBJECTIVE: To assess the value of detecting the rearrangement of mixed lineage leukemia (MLL) gene in children with acute mononuclear leukemia (AML). METHODS: Dual-color fluorescence in situ hybridization (FISH) probe was used to detect MLL gene rearrangement in 68 children with AML by interphase FISH. The results were compared with that of conventional G banding chromosomal analysis. RESULTS: Among the 68 children, 28 were detected by FISH with positive hybridization signals, with a detection rate for MLL gene rearrangement being 41.2%. Twelve (17.6%) reciprocal translocations and interruption of 11q23 were detected by G banding analysis. The difference in the detection rates between the two methods was statistically significant (P< 0.05). CONCLUSION: The sensitivity of FISH assay for MLL gene rearrangement was significantly higher than that of G banding chromosomal karyotyping. Combined use of both methods for children with AML can improve the detection rate of MLL gene rearrangements and provide crucial clues for clinical diagnosis, treatment and prognosis.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Leucemia Monocítica Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Criança , Cromossomos Humanos Par 11 , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Translocação Genética
12.
PLoS Genet ; 15(8): e1008335, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31454352

RESUMO

Genomic rearrangements (gross chromosomal rearrangements, GCRs) threatens genome integrity and cause cell death or tumor formation. At the terminus of linear chromosomes, a telomere-binding protein complex, called shelterin, ensures chromosome stability by preventing chromosome end-to-end fusions and regulating telomere length homeostasis. As such, shelterin-mediated telomere functions play a pivotal role in suppressing GCR formation. However, it remains unclear whether the shelterin proteins play any direct role in inhibiting GCR at non-telomeric regions. Here, we have established a GCR assay for the first time in fission yeast and measured GCR rates in various mutants. We found that fission yeast cells lacking shelterin components Taz1 or Rap1 (mammalian TRF1/2 or RAP1 homologues, respectively) showed higher GCR rates compared to wild-type, accumulating large chromosome deletions. Genetic dissection of Rap1 revealed that Rap1 contributes to inhibiting GCRs via two independent pathways. The N-terminal BRCT-domain promotes faithful DSB repair, as determined by I-SceI-mediated DSB-induction experiments; moreover, association with Poz1 mediated by the central Poz1-binding domain regulates telomerase accessibility to DSBs, leading to suppression of de novo telomere additions. Our data highlight unappreciated functions of the shelterin components Taz1 and Rap1 in maintaining genome stability, specifically by preventing non-telomeric GCRs.


Assuntos
Reparo do DNA , Rearranjo Gênico , Proteínas de Schizosaccharomyces pombe/metabolismo , Schizosaccharomyces/genética , Proteínas de Ligação a Telômeros/metabolismo , Quebras de DNA de Cadeia Dupla , Instabilidade Genômica , Mutação , Proteínas de Schizosaccharomyces pombe/genética , Homeostase do Telômero , Proteínas de Ligação a Telômeros/genética
13.
BMC Cancer ; 19(1): 769, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31382924

RESUMO

BACKGROUND: ROS1 rearrangements are validated drivers in lung cancer, which have been identified in a small subset (1-2%) of patients with non-small cell lung cancer (NSCLC). To date, 18 fusion genes of ROS1 have been identified in NSCLC. The ALK inhibitor (crizotinib) exhibits therapeutic effect against ROS1-rearranged NSCLC. Next-generation sequencing (NGS) technology represents a novel tool for ROS1 detection that covers many fusion genes. CASE PRESENTATION: A 55-year-old female with EGFR mutation (L858R) was diagnosed with lung adenocarcinoma, who was responsive to first-generation EGFR-tyrosine kinase inhibitor (TKI). Afterwards, she developed acquired resistance accompanied with a ROS1 rearrangement. A NGS assay showed that the tumor had a novel ROS1-ADGRG6 rearrangement generated by the fusion of exons of 1-33 of ROS1 on chr6: q22.1 to exons of 2-26 of ADGRG6 on chr6: q24.2. The patient was obviously responsive to crizotinib. CONCLUSION: We firstly identified ROS1-ADGRG6 fusion variant in NSCLC by NGS, which should be considered in further ROS1 detecting assays.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Cromossomos Humanos Par 6/genética , Crizotinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Éxons/genética , Feminino , Seguimentos , Rearranjo Gênico/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Mutação , Medicina de Precisão , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Resultado do Tratamento
14.
Int J Mol Sci ; 20(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443555

RESUMO

Carnivorous plants have the ability to capture and digest small animals as a source of additional nutrients, which allows them to grow in nutrient-poor habitats. Here we report the complete sequences of the plastid genomes of two carnivorous plants of the order Caryophyllales, Drosera rotundifolia and Nepenthes × ventrata. The plastome of D. rotundifolia is repeat-rich and highly rearranged. It lacks NAD(P)H dehydrogenase genes, as well as ycf1 and ycf2 genes, and three essential tRNA genes. Intron losses are observed in some protein-coding and tRNA genes along with a pronounced reduction of RNA editing sites. Only six editing sites were identified by RNA-seq in D. rotundifolia plastid genome and at most conserved editing sites the conserved amino acids are already encoded at the DNA level. In contrast, the N. × ventrata plastome has a typical structure and gene content, except for pseudogenization of the ccsA gene. N. × ventrata and D. rotundifolia could represent different stages of evolution of the plastid genomes of carnivorous plants, resembling events observed in parasitic plants in the course of the switch from autotrophy to a heterotrophic lifestyle.


Assuntos
Evolução Biológica , Drosera/genética , Genomas de Plastídeos , Genômica , Biologia Computacional/métodos , Drosera/parasitologia , Duplicação Gênica , Rearranjo Gênico , Genes de Plantas , Genômica/métodos , Edição de RNA
15.
Cancer Sci ; 110(10): 3382-3390, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31444835

RESUMO

Anaplastic lymphoma kinase (ALK) fusions have been recognized as a therapeutic target in non-small cell lung cancer (NSCLC). However, molecular signatures and clinical characteristics of the Chinese population with ALK-rearranged NSCLC are not well elucidated. In the present study, we carried out targeted next-generation sequencing on tissue and plasma ctDNA samples in 1688 patients with NSCLC. Overall, ALK fusions were detected in 70 patients (4.1%), and the frequencies of ALK fusions detected in tissue and plasma samples were 5.1% and 3.3%, respectively. Additionally, the prevalence of breakpoint locations for EML4-ALK fusions in ctDNA was significantly correlated with that in tumor tissues (R2  = .91, P = .045). According to age, the incidence rates of ALK fusions among young (age <45 years), middle-aged (between 45 and 70 years) and elderly (>70 years) patients were significantly different (P < .001). In 70 ALK-rearranged cases, coexistence of epidermal growth factor receptor (EGFR) alterations and ALK fusions was detected in 12 cases (17.1%) and EGFR mutations tended to coexist with non-EML4-ALK rearrangements. Notably, novel ALK fusion partners, including TRIM66, SWAP70, WNK3, ERC1, TCF12 and FBN1 were identified in the present study. Among EML4-ALK fusion variants, patients with variant V1 were younger than patients with variant V3 (P = .023), and TP53 mutations were more frequently concurrent with variant V3 compared with variant V1 (P = .009). In conclusion, these findings provide new insights into the molecular-clinical profiles of patients with ALK-rearranged NSCLC that may improve the treatment strategy of this population.


Assuntos
Quinase do Linfoma Anaplásico/genética , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Rearranjo Gênico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Estudos Prospectivos , Análise de Sequência de DNA , Translocação Genética
16.
Mol Cells ; 42(7): 512-522, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31362468

RESUMO

Chromosomes located in the nucleus form discrete units of genetic material composed of DNA and protein complexes. The genetic information is encoded in linear DNA sequences, but its interpretation requires an understanding of threedimensional (3D) structure of the chromosome, in which distant DNA sequences can be juxtaposed by highly condensed chromatin packing in the space of nucleus to precisely control gene expression. Recent technological innovations in exploring higher-order chromatin structure have uncovered organizational principles of the 3D genome and its various biological implications. Very recently, it has been reported that large-scale genomic variations may disrupt higher-order chromatin organization and as a consequence, greatly contribute to disease-specific gene regulation for a range of human diseases. Here, we review recent developments in studying the effect of structural variation in gene regulation, and the detection and the interpretation of structural variations in the context of 3D chromatin structure.


Assuntos
Cromatina/química , Variação Estrutural do Genoma , Imagem Tridimensional , Rearranjo Gênico/genética , Genoma
17.
Surg Pathol Clin ; 12(3): 687-697, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31352981

RESUMO

Acute leukemias of ambiguous lineage (ALAL) include acute undifferentiated leukemia and mixed-phenotype acute leukemia (MPAL). This article provides an overview of the diagnosis of ALAL and focuses on the data accounting for the current lineage-assignment criteria for blasts harboring more than one lineage-associated marker. In addition, the currently known molecular data are reviewed, which show that MPAL-associated gene mutations, methylation signatures, and expression profiles are a mixture of those seen in both acute myeloid leukemia and acute lymphoblastic leukemia. Finally, the prognosis and current treatments of MPAL are briefly discussed.


Assuntos
Leucemia Aguda Bifenotípica/patologia , Biomarcadores Tumorais/metabolismo , Metilação de DNA , Diagnóstico Diferencial , Rearranjo Gênico/genética , Genes Neoplásicos/genética , Humanos , Leucemia Aguda Bifenotípica/genética , Leucemia Aguda Bifenotípica/terapia , Mutação/genética , Fenótipo , Prognóstico
18.
BMC Biol ; 17(1): 55, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299961

RESUMO

BACKGROUND: The spatial organization of the mammalian genome relies upon the formation of chromatin domains of various scales. At the level of gene regulation in cis, collections of enhancer sequences define large regulatory landscapes that usually match with the presence of topologically associating domains (TADs). These domains often contain ranges of enhancers displaying similar or related tissue specificity, suggesting that in some cases, such domains may act as coherent regulatory units, with a global on or off state. By using the HoxD gene cluster, which specifies the topology of the developing limbs via highly orchestrated regulation of gene expression, as a paradigm, we investigated how the arrangement of regulatory domains determines their activity and function. RESULTS: Proximal and distal cells in the developing limb express different levels of Hoxd genes, regulated by flanking 3' and 5' TADs, respectively. We characterized the effect of large genomic rearrangements affecting these two TADs, including their fusion into a single chromatin domain. We show that, within a single hybrid TAD, the activation of both proximal and distal limb enhancers globally occurred as when both TADs are intact. However, the activity of the 3' TAD in distal cells is generally increased in the fused TAD, when compared to wild type where it is silenced. Also, target gene activity in distal cells depends on whether or not these genes had previously responded to proximal enhancers, which determines the presence or absence of H3K27me3 marks. We also show that the polycomb repressive complex 2 is mainly recruited at the Hox gene cluster and can extend its coverage to far-cis regulatory sequences as long as confined to the neighboring TAD structure. CONCLUSIONS: We conclude that antagonistic limb proximal and distal enhancers can exert their specific effects when positioned into the same TAD and in the absence of their genuine target genes. We also conclude that removing these target genes reduced the coverage of a regulatory landscape by chromatin marks associated with silencing, which correlates with its prolonged activity in time.


Assuntos
Cromatina/genética , Rearranjo Gênico/genética , Genes Homeobox/genética , Genoma , Animais , Camundongos
19.
Drugs ; 79(12): 1277-1286, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31313100

RESUMO

ROS1 gene rearrangements exist in 1-2% of non-small cell lung cancers, typically occurring in younger, never or light smokers with adenocarcinoma. ROS1 gene fusions are potent oncogenic drivers, the presence of which results in the susceptibility of tumours to ROS1-targeted therapy. Crizotinib was the first tyrosine kinase inhibitor to demonstrate activity in ROS1-rearranged lung cancer, and remains the recommended first-line therapy for patients with advanced ROS1-rearranged non-small cell lung cancer. Despite excellent initial responses to crizotinib, the majority of patients develop disease progression, which may be intracranial or extracranial. Identification of resistance mechanisms to crizotinib, and newer generation tyrosine kinase inhibitors with increased potency against ROS1 and ROS1-resistance mutations, and improved intracranial activity are under evaluation in clinical trials. In this review, we discuss ROS1 rearrangements in non-small cell lung cancer, and provide an update on targeting ROS1-rearranged non-small cell lung cancer with crizotinib and newer generation tyrosine kinase inhibitors.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/uso terapêutico , Rearranjo Gênico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Barreira Hematoencefálica/metabolismo , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Terapia de Alvo Molecular , Mutação , Permeabilidade , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética
20.
Nat Genet ; 51(8): 1272-1282, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31308546

RESUMO

Chromatin topology is intricately linked to gene expression, yet its functional requirement remains unclear. Here, we comprehensively assessed the interplay between genome topology and gene expression using highly rearranged chromosomes (balancers) spanning ~75% of the Drosophila genome. Using transheterozyte (balancer/wild-type) embryos, we measured allele-specific changes in topology and gene expression in cis, while minimizing trans effects. Through genome sequencing, we resolved eight large nested inversions, smaller inversions, duplications and thousands of deletions. These extensive rearrangements caused many changes to chromatin topology, disrupting long-range loops, topologically associating domains (TADs) and promoter interactions, yet these are not predictive of changes in expression. Gene expression is generally not altered around inversion breakpoints, indicating that mis-appropriate enhancer-promoter activation is a rare event. Similarly, shuffling or fusing TADs, changing intra-TAD connections and disrupting long-range inter-TAD loops does not alter expression for the majority of genes. Our results suggest that properties other than chromatin topology ensure productive enhancer-promoter interactions.


Assuntos
Cromatina/genética , Cromossomos de Insetos/genética , Drosophila melanogaster/genética , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Rearranjo Gênico , Genoma de Inseto , Animais , Mapeamento Cromossômico , Feminino , Masculino , Regiões Promotoras Genéticas
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