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We here describe a leukemogenic role of the homeobox gene UNCX, activated by epigenetic modifications in acute myeloid leukemia (AML). We found the ectopic activation of UNCX in a leukemia patient harboring a t(7;10)(p22;p14) translocation, in 22 of 61 of additional cases [a total of 23 positive patients out of 62 (37.1%)], and in 6 of 75 (8%) of AML cell lines. UNCX is embedded within a low-methylation region (canyon) and encodes for a transcription factor involved in somitogenesis and neurogenesis, with specific expression in the eye, brain, and kidney. UNCX expression turned out to be associated, and significantly correlated, with DNA methylation increase at its canyon borders based on data in our patients and in archived data of patients from The Cancer Genome Atlas. UNCX-positive and -negative patients displayed significant differences in their gene expression profiles. An enrichment of genes involved in cell proliferation and differentiation, such as MAP2K1 and CCNA1, was revealed. Similar results were obtained in UNCX-transduced CD34+ cells, associated with low proliferation and differentiation arrest. Accordingly, we showed that UNCX expression characterizes leukemia cells at their early stage of differentiation, mainly M2 and M3 subtypes carrying wild-type NPM1 We also observed that UNCX expression significantly associates with an increased frequency of acute promyelocytic leukemia with PML-RARA and AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 classes, according to the World Health Organization disease classification. In summary, our findings suggest a novel leukemogenic role of UNCX, associated with epigenetic modifications and with impaired cell proliferation and differentiation in AML.
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Diferenciação Celular/genética , Expressão Ectópica do Gene , Epigênese Genética , Proteínas de Homeodomínio/genética , Células Mieloides/citologia , Células Mieloides/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proliferação de Células , Biologia Computacional/métodos , DNA (Citosina-5-)-Metiltransferases , Metilação de DNA , DNA Metiltransferase 3A , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Mutação , Nucleofosmina , Translocação Genética , Adulto JovemRESUMO
The genetic lesions identified to date do not fully recapitulate the molecular pathogenesis of chronic lymphocytic leukemia (CLL) and do not entirely explain the development of severe complications such as chemorefractoriness. In the present study, BIRC3, a negative regulator of noncanonical NF-κB signaling, was investigated in different CLL clinical phases. BIRC3 lesions were absent in monoclonal B-cell lymphocytosis (0 of 63) and were rare in CLL at diagnosis (13 of 306, 4%). Conversely, BIRC3 disruption selectively affected 12 of 49 (24%) fludarabine-refractory CLL cases by inactivating mutations and/or gene deletions that distributed in a mutually exclusive fashion with TP53 abnormalities. In contrast to fludarabine-refractory CLL, progressive but fludarabine-sensitive patients were consistently devoid of BIRC3 abnormalities, suggesting that BIRC3 genetic lesions associate specifically with a chemorefractory phenotype. By actuarial analysis in newly diagnosed CLL (n = 306), BIRC3 disruption identified patients with a poor outcome similar to that associated with TP53 abnormalities and exerted a prognostic role that was independent of widely accepted clinical and genetic risk factors. Consistent with the role of BIRC3 as a negative regulator of NF-κB, biochemical studies revealed the presence of constitutive noncanonical NF-κB activation in fludarabine-refractory CLL patients harboring molecular lesions of BIRC3. These data identify BIRC3 disruption as a recurrent genetic lesion of high-risk CLL devoid of TP53 abnormalities.
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Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Inibidoras de Apoptose/genética , Leucemia Linfocítica Crônica de Células B/genética , Proteína Supressora de Tumor p53/genética , Vidarabina/análogos & derivados , Idoso , Proteína 3 com Repetições IAP de Baculovírus , Western Blotting , Análise Mutacional de DNA , Feminino , Humanos , Hibridização in Situ Fluorescente , Proteínas Inibidoras de Apoptose/metabolismo , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ubiquitina-Proteína Ligases , Vidarabina/uso terapêuticoRESUMO
The patient had been diagnosed with polycythemia vera (PV) in 1999, at the age of 61, according to the criteria of the Polycythemia Vera Study Group (PVSG) on the basis of the increased red cell mass by isotope determination, normal oxygen saturation, low plasma erythropoietin level, presence of endogenous erythroid colonies (EEC), and splenomegaly. Histopathology of bone marrow biopsy was also consistent with polycythemia vera with no evidence of increased reticulin fibrosis. A karyotype analysis was not performed at that time. He had been treated initially with phlebotomies and then with hydroxyurea with the aim to obtain a better control of hematocrit; he was under low-dose aspirin. In 2009, 10 years after the diagnosis, while the patient was still being treated with hydroxyurea and phlebotomies, he noticed worsening of general conditions and fatigue, and the appearance of night sweats; he also reported that his spleen volume had increased rapidly in the past few months. He complained of severe pruritus especially after (but not limited to) a shower. He was referred to our center for further evaluation. At presentation, his blood counts were as follows: hemoglobin 157 g/L, hematocrit 54.7%, leukocytes 13.1 × 109 /L, platelets 238 × 109 /L, LDH 856 U/L (normal upper limit, 250 U/L). Blood film examination showed neutrophilia (8.9 × 109 /L) but immature myeloid cells and nucleated erythroblasts were absent. The spleen was 14 cm below the left costal margin, the liver was at 4 cm below the right costal margin. He was found to harbor the JAK2V617F mutation with an allele burden of 85% and the circulating CD34⺠cell count was 14 × 106 /L. A bone marrow biopsy showed the presence of hyperplasia of myeloid and erythroid lineages, increased number of scattered megakarocytes without overt morphologic abnormalities; reticulin fibrosis was grade 1 according to the European classification. On these basis, we considered the patient as presenting the features of PV according to the 2008 WHO classification of myeloid neoplasms associated with grade 1 reticulin fibrosis.
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Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 6/genética , Cariótipo , Policitemia Vera/genética , Translocação Genética , Deleção Cromossômica , Cromossomos Humanos Par 15/ultraestrutura , Cromossomos Humanos Par 6/ultraestrutura , Terapia Combinada , Progressão da Doença , Células Eritroides/patologia , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Hiperplasia , Hibridização in Situ Fluorescente , Janus Quinase 2/genética , Masculino , Megacariócitos/patologia , Pessoa de Meia-Idade , Células Mieloides/patologia , Flebotomia , Mutação Puntual , Policitemia Vera/sangue , Policitemia Vera/complicações , Policitemia Vera/tratamento farmacológico , Policitemia Vera/patologia , Policitemia Vera/terapia , Mielofibrose Primária/etiologia , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Reticulina/análiseRESUMO
The continuous increase in life expectancy leads to progressive population ageing, especially in most developed countries. A healthy diet and better consumption of tailored functional foods may represent one of the strategies to postpone or slow down age-related decrements, thus increasing healthy ageing and reducing healthcare costs. This research aimed to explore elderly people's (>65 years old) eating habits and assess their awareness of food-health correlation. In total, 511 Italian seniors answered a CATI (computer-assisted telephone interviewing) questionnaire through a deep, telephone interview to collect information about dietary habits, healthy food awareness, and inclination for functional foods. The elderly were divided into four groups according to gender and age: Early Elderly Female (n = 130), Early Elderly Men (n = 109), Late Elderly Female (n = 157), and Late Elderly Men (n = 115). The groups provided a positive self-assessment of health status and individual diet healthiness, which were both considered over "good enough" (5 on 10-point scale) and showed food consumption habits in line with the Mediterranean Diet (MD) principles. The daily diet was based on fruits, vegetables, bread, and pasta, with extra virgin olive oil as the main fat source, all over "often" consumed (4 on 5-point scale). Old people also showed awareness of different food's healthy properties. Specifically, females were more aware of food's impact on health, considered close to "extremely healthy" (9 on 10-point scale), and strictly followed a MD. Participants also expressed optimistic expectations about functional food efficiency, evaluated as close to "extremely desirable" (8 or 9 on 10-point scale), against age-related problems, highlighting the most important as diabetes, overweight, intestine problems, and low mood. The interviewed elderly were also involved in virtual functional food co-creation, indicating through a basic matrix which, among the most familiar foods, could be the ideal functional food, focusing on fruitsand vegetables. A pleasant odor/flavor, a liquid texture, and a warm serving temperature rather than cold characterized the virtual functional food created. Other positive attributes were liquid and thickness, while acidity and bitterness were among the least desired traits. These findings show how elderly people, despite predictable age-related sensory and cognitive loss, when properly involved and guided, can help envision foods that fit their needs and desires.
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Dieta Mediterrânea , Alimento Funcional , Masculino , Humanos , Feminino , Idoso , Comportamento Alimentar , Dieta , Verduras , Itália , Telefone , ComputadoresRESUMO
Double minutes (dmin) and homogeneously staining regions (hsr) are the cytogenetic hallmarks of genomic amplification in cancer. Different mechanisms have been proposed to explain their genesis. Recently, our group showed that the MYC-containing dmin in leukemia cases arise by excision and amplification (episome model). In the present paper we investigated 10 cell lines from solid tumors showing MYCN amplification as dmin or hsr. Particularly revealing results were provided by the two subclones of the neuroblastoma cell line STA-NB-10, one showing dmin-only and the second hsr-only amplification. Both subclones showed a deletion, at 2p24.3, whose extension matched the amplicon extension. Additionally, the amplicon structure of the dmin and hsr forms was identical. This strongly argues that the episome model, already demonstrated in leukemias, applies to solid tumors as well, and that dmin and hsr are two faces of the same coin. The organization of the duplicated segments varied from very simple (no apparent changes from the normal sequence) to very complex. MYCN was always overexpressed (significantly overexpressed in three cases). The fusion junctions, always mediated by nonhomologous end joining, occasionally juxtaposed truncated genes in the same transcriptional orientation. Fusion transcripts involving NBAS (also known as NAG), FAM49A, BC035112 (also known as NCRNA00276), and SMC6 genes were indeed detected, although their role in the context of the tumor is not clear.
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Amplificação de Genes , Genes myc , Neoplasias/genética , Citogenética , Hibridização in Situ Fluorescente , Cariotipagem , Dados de Sequência Molecular , Deleção de SequênciaRESUMO
Honey is a worldwide known and appreciated food product. Its appreciation by consumers is due to both its nutritional properties and the extremely reduced processing. The floral origin, color, aroma and taste are key factors in determining the quality of honey. Nevertheless, rheological properties, as crystallization rate, play a fundamental role in the perceived overall quality. Indeed, crystallized honey is often considered of poor quality by consumers, but a fine-grained or creamy texture is becoming interesting from the producers' side. The purpose of this study was to investigate textural and aromatic properties and consumers' perception and acceptance of two monofloral honeys that were differently crystallized. Liquid and creamy samples were obtained from crystallized samples. Physico-chemical, descriptive and dynamic sensory analysis, as well as consumer and CATA tests, were conducted on the three honey textures. The physico-chemical analysis well-discriminated the crystallization levels and evidenced that, although the honey variety was different, the textural properties of the creamy samples are very similar. Crystallization was shown to affect the honey sensory perceptions: liquid samples were sweeter, but less aromatic. Consumer tests allowed the validation of panel data and confirmed consumers' higher appreciation for liquid and creamy honey.
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The containment measures due to the COVID-19 pandemic affected food-related activities, influencing dietary behavior, food habits, and dietary choices. This study aimed to compare the relationship between food involvement and dietary choices before and during the pandemic, investigating the role played by food in dietary habits. Responses given by 2773 Italian consumers to an online survey were studied through the Food Involvement Scale (FIS) and correlated to eating habits. FIS scores were then used to explain the importance given to food in circumstances related to well-being, health, and protection against COVID-19 and used to study the relationship between FIS and bioactive compound knowledge, use, and efficacy against COVID-19. The consumers more involved in food issues recognized the importance of food in circumstances related to well-being, health, and protection against COVID-19 and improved their diet during the pandemic. Moreover, consumers who gave more importance to food also revealed higher attention to the use of healthy substances, such as bioactive compounds, considering them effective against COVID-19. These results showed that food experiencing and involvement could be important elements to promote healthy dietary habits that are essential to maintain physical and mental health during emergency periods such as the COVID-19 pandemic.
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COVID-19 , Pandemias , COVID-19/epidemiologia , Comportamento Alimentar , Preferências Alimentares , Humanos , SARS-CoV-2RESUMO
Demand for eggs from laying hens is increasing as the world population continues to grow. The use of insects as animal feed is a strategic opportunity to find a new innovative, economic and sustainable source of protein. The aim of this study was to evaluate the Italian consumer inclination for eggs produced with the use of insect-fed hens. The investigation on consumers' readiness to adopt eggs from insect-fed hens was carried out through an online survey conducted on 510 participants. Survey results outlined four different clusters on the basis of the willingness to buy/eat eggs fed with insects: "ready" (40.1%), "environmentalist" (24.3%), "cautious" (21.7%), and "reluctant" (13.9%). "Ready", "environmentalist", and "cautious" were quite favorable to the use of insects as feed stuffs and share drivers for product choice: cheap, organic, and with an explicit indication of use of insects. On the other hand, for the "reluctant", the diet based on insects was the main negative factor influencing product acceptance. This cluster also showed the highest level of neophobia. Italian consumers showed a considerable level of readiness to accept insects as feed material for egg production, which should be reinforced with further information on the origin and the environmental benefit of using insects.
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Common beans (Phaseolus vulgaris L.) are an important source of nutrients with beneficial effects on human health. However, they contain lectins, that limit the direct use of flour in food preparations without thermal treatment, and phytic acid, that reduces mineral cation bioavailability. The objectives of this research were: to obtain biofortified snacks and a cream using an untreated common bean flour devoid of active lectins (lec-) and with reduced content of phytic acid (lpa) and to evaluate the sensorial appreciation for these products. The main results of the present work were: the products with the lpa lec- flour did not retain residual hemagglutinating activity due to lectins; they showed higher residual α-amylase inhibitor activity (from 2.2 to 135 times), reduced in vitro predicted glycemic index (about 5 units reduction) and increased iron bioavailability compared to the products with wild type flour; products with common bean flour were less appreciated than the reference ones without this flour, but the presence of an intense umami taste can be a positive attribute. Results confirmed that the use of the lpa lec- flour has important advantages in the preparation of safe and nutritionally improved products, and provide useful information to identify target consumers, such as children and elderly people.
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Análise de Alimentos , Manipulação de Alimentos/métodos , Valor Nutritivo , Phaseolus/química , Sensação , Culinária , HumanosAssuntos
Antígenos CD7 , Cromossomos Humanos Par 4/genética , Regulação Leucêmica da Expressão Gênica , Proteínas de Homeodomínio/biossíntese , Leucemia Mieloide Aguda , Translocação Genética , Idoso , Feminino , Proteínas de Homeodomínio/genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , MasculinoAssuntos
Proteínas de Ciclo Celular/genética , Cromossomos Humanos/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Fator de Transcrição PAX5/genética , Proteínas/genética , Aberrações Cromossômicas , Proteínas do Citoesqueleto , Humanos , Hibridização in Situ Fluorescente , Proteínas de Ligação a Poli-ADP-Ribose , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Prognóstico , Fatores de Transcrição , Translocação Genética/genética , Ubiquitina-Proteína LigasesRESUMO
The Mediterranean diet (MD) is associated with many health benefits. The association between the MD and food neophobia (FN) is still unexplored in adults. The present cross-sectional study was aimed to explore the relationships between adherence to the MD, FN, and sociodemographic variables in a large Italian cohort. Familiarity and frequency use (FFI) of prototypical and non-prototypical Mediterranean foods were used to calculate a new adherence index: the Italian Taste Mediterranean Index (ITMI). The FFI of all Mediterranean foods increased with age, while butter, soft drinks, red/cured meat, and sweets were more common in younger people. Accordingly, ITMI increased with age (F2,2384 = 54.11; p < 0.0001). Women recorded a higher ITMI (6.70) than men (6.10). Individuals with high FN showed higher FFI for soft drinks and sweets and lower ones for most typical MD foods, than individuals with low FNs. A decrease of ITMI was recorded with the increase of the FN(F2,2384 = 22.84; p < 0.0001). With ageing, ITMI increased even in individuals with a high FN. The results suggest that FN may negatively affect adherence to the MD, lowering its potential health benefits, in the adult population. Monitoring of food habits, dietary education, and anxiety management, may be valuable tools to control FN and support the adherence to the MD.
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Fatores Etários , Transtorno Alimentar Restritivo Evitativo , Dieta Mediterrânea , Meio Ambiente , Fatores Sexuais , Adolescente , Adulto , Animais , Estudos Transversais , Comportamento Alimentar , Feminino , Peixes , Frutas , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente/psicologia , Cooperação do Paciente/estatística & dados numéricos , Verduras , Adulto JovemRESUMO
Acute lymphoblastic leukemia (ALL) is the most frequent pediatric cancer. Fusion genes are hallmarks of ALL, and they are used as biomarkers for risk stratification as well as targets for precision medicine. Hence, clinical diagnostics pursues broad and comprehensive strategies for accurate discovery of fusion genes. Currently, the gold standard methodologies for fusion gene detection are fluorescence in situ hybridization and polymerase chain reaction; these, however, lack sensitivity for the identification of new fusion genes and breakpoints. In this study, we implemented a simple operating procedure (OP) for detecting fusion genes. The OP employs RNA CaptureSeq, a versatile and effortless next-generation sequencing assay, and an in-house as well as a purpose-built bioinformatics pipeline for the subsequent data analysis. The OP was evaluated on a cohort of 89 B-cell precursor ALL (BCP-ALL) pediatric samples annotated as negative for fusion genes by the standard techniques. The OP confirmed 51 samples as negative for fusion genes, and, more importantly, it identified known (KMT2A rearrangements) as well as new fusion events (JAK2 rearrangements) in the remaining 38 investigated samples, of which 16 fusion genes had prognostic significance. Herein, we describe the OP and its deployment into routine ALL diagnostics, which will allow substantial improvements in both patient risk stratification and precision medicine.
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The identification of chromosome 1 translocations and deletions is a rare and poorly investigated event in chronic lymphocytic leukemia (CLL). Nevertheless, the identification of novel additional molecular alterations is of great interest, opening to new prognostic and therapeutic strategies for such heterogeneous hematological disease. We here describe a patient affected by CLL with a mutated IGHV status, showing a balanced t(1;3)(q23.1;q21.3) translocation and a der(18)t(1;18)(q24.2;p11.32), accompanying the recurrent 13q14 heterozygous deletion in all analyzed cells at onset. By combining whole-genome sequencing, SNP array, RNA sequencing, and FISH analyses, we defined a 1q23.1 biallelic minimally deleted region flanking translocations breakpoints at both derivative chromosome 1 homologues. The deletion resulted in the downregulation of the Fc receptor-like family genes FCRL1, FCRL2, and FCRL3 and in the lack of expression of FCRL5, observed by RT-qPCR. The mutational status of TP53, NOTCH1, SF3B1, MYD88, FBXW7, and XPO1 was investigated by targeted next-generation sequencing, detecting a frameshift deletion within NOTCH1 (c.7544_7545delCT). We hypothesize a loss of tumor suppressor function for FCRL genes, cooperating with NOTCH1 mutation and 13q14 genomic loss in our patient, both conferring a negative prognosis, independently from the known biological prognostic factors of CLL.
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Cromossomos Humanos 1-3/genética , Regulação para Baixo , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/patologia , Receptores Fc/biossíntese , Deleção de Sequência , Translocação Genética , Idoso , Humanos , Masculino , Patologia Molecular , PrognósticoRESUMO
In the original version of this Article, the affiliation details for Giovanni Martinelli were incorrectly given as 'Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138, Bologna, Italy' and it should have been given as 'Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy and not Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138, Bologna, Italy.'Furthermore, the original version of this Article contained an error in the spelling of the authors Alberto L'Abbate and Pietro D'Addabbo, an acute accent was used instead of an apostrophe for these authors names.These errors have now been corrected in both the PDF and HTML versions of the Article.
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Double minutes (dmin), homogeneously staining regions, and ring chromosomes are vehicles of gene amplification in cancer. The underlying mechanism leading to their formation as well as their structure and function in acute myeloid leukemia (AML) remain mysterious. We combined a range of high-resolution genomic methods to investigate the architecture and expression pattern of amplicons involving chromosome band 8q24 in 23 cases of AML (AML-amp). This revealed that different MYC-dmin architectures can coexist within the same leukemic cell population, indicating a step-wise evolution rather than a single event origin, such as through chromothripsis. This was supported also by the analysis of the chromothripsis criteria, that poorly matched the model in our samples. Furthermore, we found that dmin could evolve toward ring chromosomes stabilized by neocentromeres. Surprisingly, amplified genes (mainly PVT1) frequently participated in fusion transcripts lacking a corresponding DNA template. We also detected a significant overexpression of the circular RNA of PVT1 (circPVT1) in AML-amp cases versus AML with a normal karyotype. Our results show that 8q24 amplicons in AML are surprisingly plastic DNA structures with an unexpected association to novel fusion transcripts and circular RNAs.
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Amplificação de Genes/genética , Genes myc/genética , Leucemia Mieloide Aguda/genética , Transcrição Gênica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Bandeamento Cromossômico/métodos , Cromossomos Humanos Par 8/genética , Feminino , Genômica/métodos , Humanos , Cariotipagem/métodos , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/genética , Adulto JovemRESUMO
We set up a diagnostic double-color double-fusion fluorescence in situ hybridization (DCDF-FISH) assay to investigate a case of a de novo acute myeloid leukemia (AML)-M4 bearing an inv(11)(p15q22). DCDF-FISH detected the NUP98-DDX10 rearrangement as two fusion signals, at the short and the long arms of the inv(11). Reverse transcription-polymerase chain reaction (RT-PCR) and cloning experiments confirmed the NUP98-DDX10 fusion and identified two splicing fusion isoforms: the known "type II fusion," originating from the fusion of NUP98 exon 14 to DDX10 exon 7 and a new in-frame fusion transcript between NUP98 exon 15 and DDX10 exon 7, which we termed "type III fusion."
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Inversão Cromossômica , Cromossomos Humanos Par 11/genética , RNA Helicases DEAD-box/genética , Leucemia Mieloide/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Doença Aguda , Adulto , Sequência de Aminoácidos , Sequência de Bases , Bandeamento Cromossômico , Éxons/genética , Humanos , Hibridização in Situ Fluorescente/métodos , Cariótipo , Masculino , Dados de Sequência Molecular , Isoformas de Proteínas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição GênicaRESUMO
To provide new insights into the genomic profile of desmoplastic round cell tumors (DSRCT), we applied fluorescence in situ hybridization (FISH) and metaphase comparative genomic hybridization (M-CGH) to two newly diagnosed cases. FISH detected multiple subclones bearing one to three copies of der(11)t(11;22)(p13;q12) and/or der(22)t(11;22)(p13;q12) in both patients. This peculiar genomic imbalance might result from derivative chromosome duplication due to non-disjunction and/or mitotic recombination between normal and derivative chromosomes 11 and 22. Concomitant loss of normal chromosomes (i.e., 11 in patient 1 and 22 in patient 2) caused loss of the WT1 or EWSR1 wild-type allele. M-CGH identified other genomic imbalances: gain at chromosome 3 in both cases and chromosome 5 polysomy in patient 1. Common genomic events (i.e., trisomy 3 and extra EWSR1-WT1 and WT1-EWSR1 copies) probably contributed to disease pathogenesis and/or evolution of DSRCT. Our study demonstrated that an integrated molecular cytogenetic approach identified EWSR1-WT1 cooperating molecular events and genetic markers for prognosis. Thus, FISH and M-CGH might well be applied in a large series of patients to elucidate the genomic background of DSRCT.
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Proteínas de Ligação a Calmodulina/genética , Tumor Desmoplásico de Pequenas Células Redondas/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Ligação a RNA/genética , Proteínas WT1/genética , Adulto , Proteínas de Ligação a Calmodulina/metabolismo , Tumor Desmoplásico de Pequenas Células Redondas/diagnóstico , Tumor Desmoplásico de Pequenas Células Redondas/metabolismo , Tumor Desmoplásico de Pequenas Células Redondas/patologia , Humanos , Hibridização in Situ Fluorescente , Masculino , Proteínas de Fusão Oncogênica/metabolismo , Prognóstico , Proteína EWS de Ligação a RNA , Proteínas de Ligação a RNA/metabolismo , Translocação Genética , Proteínas WT1/metabolismo , Adulto Jovem , Dedos de ZincoRESUMO
We describe a case of acute myeloid leukemia M5 showing a balanced t(2;10) (q31;p12) translocation. This has never been described before as the sole cytogenetic abnormality in a bone marrow cell clone at onset. Using fluorescence in situ hybridization with properly designed bacterial artificial chromosome probes, we mapped the breakpoint regions on both derivative chromosomes 2 and 10: der(2) and der(10), respectively. The MPP7 gene, disrupted by the breakpoint on chromosome 10, was juxtaposed upstream of both HNRNA3 and NFE2L2 genes on chromosome 2, without the formation of any fusion gene. Using real-time quantitative polymerase chain reaction, we tested the possible disregulation of any of the breakpoint-associated genes as a consequence of the translocation, but we found no statistically significant alteration. Considering the potential role of this clonal cytogenetic abnormality in leukemogenesis, we speculate that this translocation could have an impact on additional genes mapping outside the breakpoint regions. However, the limited amount of RNA material available prevented us from testing this hypothesis in this present case.