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1.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064196

RESUMO

BACKGROUND: Chimeric antigen receptor (CAR) T-cells are changing the therapeutic landscape of hematologic malignancies. Severe side effects include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but prolonged cytopenia has also been reported. The underlying mechanism for prolonged cytopenia is poorly understood so far. CASES: Severe pancytopenia with grade 2-3 anemia was marked 2-3 months after treatment. Laboratory evaluation revealed undetectable levels of haptoglobin with increased reticulocyte counts. Coomb's tests were negative, no schistocytes were detected on blood smear, and infectious causes were ruled out. Increased erythropoiesis without lymphoma infiltration was noted on bone marrow biopsy. A spontaneous increase in haptoglobin and hemoglobin levels was observed after several weeks. For one patient, peripheral CAR-T levels were monitored over time. We observed a decline at the same time as hemoglobin levels began to rise, implying a potential causality. CONCLUSION: To our knowledge, we describe the first two cases of Coombs-negative hemolytic anemia after CAR-T treatment for B-cell lymphoma. We encourage routine monitoring for hemolytic anemia after CAR-T treatment and also encourage further investigations on the underlying mechanism.


Assuntos
Anemia Hemolítica/etiologia , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Pancitopenia/etiologia , Receptores de Antígenos Quiméricos/imunologia , Feminino , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Humanos , Linfoma/genética , Masculino , Pessoa de Meia-Idade
3.
Medicine (Baltimore) ; 100(10): e24010, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33725812

RESUMO

RATIONALE: Renal-occupying lesions positive for urine fluorescence in situ hybridization (FISH) are usually considered urothelial carcinomas. Here, we describe 2 cases of renal metastases with chromosome duplications in urine exfoliated cells. PATIENT SYMPTOMS: Patient 1, a 56-year-old male with a history of esophageal cancer, was admitted to our hospital on May 2017 after presenting with right back pain with microscopic hematuria for 1 month. Magnetic resonance imaging (MRI) showed right renal space-occupying lesions (5.4 cm × 4.6 cm) and multiple enlarged lymph nodes in the right renal hilum and retroperitoneum. The cystoscopy results were negative, and FISH analysis of urine exfoliated cells was positive, indicative of chromosome 3, 7, and 17 amplifications. Patient 2 was a 50-year-old male who was admitted to our hospital on May 2019 with no obvious cause of abdominal pain and abdominal distension (lasting for 7 days), with a serum creatinine level of 844 µmol/L. Patient 2 had no hematuria or fever, and MRI showed left renal inferior and medial space-occupying lesions, and multiple mesenteric nodules at the junction of the left adrenal gland, retroperitoneum, abdomen, and pelvis, which were partially fused. The tumor lesions were approximately 3.1 cm × 2.3 cm in size. The urine FISH results were positive, indicating chromosome 3, 7, and 17 amplifications. DIAGNOSES: Both patients were diagnosed with renal tumors with unknown pathology. INTERVENTIONS: Patient 1 underwent laparoscopic resection of the kidney and ureter, and sleeve cystectomy. The postoperative pathological diagnosis was metastatic keratinized squamous cell carcinoma, with squamous cell carcinoma in the right hilar lymph node. Histological FISH of the primary esophageal cancer and renal metastases were consistent with the urine FISH test results. Patient 2 underwent a biopsy of the left renal inferior and retroperitoneal areas, and was diagnosed with diffuse large B-cell lymphoma. OUTCOMES: Patient 1 survived 6 months after urological surgery. After treating patient 2 with the R-CHOP regimen and kinase inhibitors, his renal function recovered significantly and the mass become undetectable. LESSONS: Our results imply that FISH-positive renal occupying lesions should be considered as potential renal metastases with chromosome aberrations when making a differential diagnosis.


Assuntos
Neoplasias Esofágicas/patologia , Neoplasias Renais/diagnóstico , Linfoma/patologia , Neoplasias Retroperitoneais/patologia , Duplicação Cromossômica , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/urina , Esôfago/diagnóstico por imagem , Humanos , Hibridização in Situ Fluorescente , Rim/diagnóstico por imagem , Rim/patologia , Rim/cirurgia , Neoplasias Renais/genética , Neoplasias Renais/secundário , Neoplasias Renais/urina , Biópsia Líquida/métodos , Linfonodos/diagnóstico por imagem , Linfoma/genética , Linfoma/urina , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias Retroperitoneais/genética , Neoplasias Retroperitoneais/urina , Espaço Retroperitoneal/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Urinálise/métodos
4.
Toxicol Appl Pharmacol ; 418: 115491, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33737021

RESUMO

Pyrazole or 1,2-Diazole is a five-membered heteroaromatic ring with two nitrogen atoms which is widely used in pharmacological research and organic synthesis. Several natural and synthetic pyrazole derivatives possess anti-cancer potential and some of them have underwent clinical trials. In this aspect, an investigation into the efficiency of the pyrazole nucleus to inhibit the growth and progression of various cancer cell lines/ experimental tumours would help in giving a better clarity to the anti-cancer behaviour of pyrazole containing drugs. This paper investigates the efficiency of pyrazole against Dalton's Lymphoma Ascites (DLA) cell line. Pyrazole inhibited the growth of DLA cells in vitro by committing them towards apoptosis. In vitro results were consistent in DLA induced murine solid tumour in vivo systems. Drug-treatment improved survival, reduced tumour loads, stabilized body weights and improved the haematological and serum biochemical parameters of DLA solid tumour bearing mice, thereby improving their overall survivability. Drug administration contained the aggravation of solid tumour by targeted downregulation of Cyclin-D1 and Ki-67. In addition, the mRNA expression levels of anti-apoptotic genes, BCL-2 and BCL-XL were downregulated in solid tumours, corroborating the in vitro results that pyrazole encourage apoptotic cell death in DLA cells. The new findings establish pyrazole as a potential anti-cancer drug candidate. The results must encourage future investigations into the efficacy of the drug against various cancer types.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ascite/tratamento farmacológico , Ciclina D1/metabolismo , Antígeno Ki-67/metabolismo , Linfoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirazóis/farmacologia , Proteína bcl-X/metabolismo , Animais , Ascite/genética , Ascite/metabolismo , Ascite/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Linfoma/genética , Linfoma/metabolismo , Linfoma/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-bcl-2/genética , Transdução de Sinais , Proteína bcl-X/genética
5.
Nanotoxicology ; 15(3): 418-432, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33710943

RESUMO

The increasing medical and food applications of silver nanoparticles (AgNPs) raise concerns about their safety, including the potential health consequences of human exposure. Previous studies found that AgNPs were negative in the Ames test due to both their microbicidal activity and the inability of nanoparticles to penetrate bacterial cell walls. Thus, the mutagenicity of AgNPs is still not completely clear, though they do induce chromosome damage, as suggested by many previous genotoxicity studies. In this study, whole-genome sequencing (WGS) was used to analyze the mutagenicity of AgNPs in mouse lymphoma cells expanded from single-cell clones. The cells were treated with AgNPs, 4-nitroquinolone-1-oxide (4-NQO) as the positive control, and vehicle controls. Both AgNPs and 4-NQO significantly increased mutation frequencies over their concurrent controls by 1.12-fold and 4.89-fold with mutation rates at 4-fold and 130-fold, respectively. AgNP-induced mutations mainly occurred at G:C sites with G:C > T:A transversions, G:C > A:T transitions, and deletions as the most commonly observed mutations. AgNPs also induced higher fold changes in tandem mutations. The results suggest that the WGS mutation assay conducted here can detect the low-level mutagenicity of AgNPs, providing substantial support for the use of the WGS method as a possible alternative assay with respect to the mutagenic assessment of nanomaterials.


Assuntos
Linfoma/patologia , Nanopartículas Metálicas/toxicidade , Mutagênicos/toxicidade , Prata/química , Sequenciamento Completo do Genoma/métodos , Animais , Dano ao DNA/efeitos dos fármacos , Humanos , Linfoma/genética , Camundongos , Mutagênese/efeitos dos fármacos , Testes de Mutagenicidade/métodos , Mutação/efeitos dos fármacos , Prata/toxicidade
6.
Pathologe ; 42(2): 241-251, 2021 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-33575888

RESUMO

Malignant lymphomas are derived from a common progenitor cell with a unique rearrangement of immunoglobulin or T­cell receptor genes. Polymerase chain reaction (PCR)-based analyses allow detection of the clone and are an important adjunct for the diagnosis of difficult lymphoproliferations, e.g. for the discrimination of reactive versus malignant lesions. Further applications are detection of disease dissemination and evaluation of the clonal relationship of two lymphomas. However, clonality analysis is not a stand-alone test and must always be considered in context with clinical, histological and immunophenotypic data. For the correct use of clonality analysis, comprehensive knowledge of the biological basis, technical requirements and interpretation are needed in order to avoid incorrect conclusions.


Assuntos
Linfoma , Células Clonais , Humanos , Linfoma/genética , Reação em Cadeia da Polimerase
7.
Mol Biol Rep ; 48(2): 1801-1817, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33523370

RESUMO

Previous literature supports the variations in microRNAs expression levels among lymphoma patients due to EBV infection. These alterations can be observed in both EBV-encoded-microRNAs and EBV-induced cellular microRNAs. Moreover, changes in the microRNA profile could be significant in disease progression. This study aimed to assess published literature to obtain a microRNA profile for both EBV-encoded microRNAs and EBV-induced cellular microRNAs among lymphoma patients. We searched common available electronic databases by using relevant keywords. The result demonstrated that EBV infection could alter the microRNA expression levels among lymphoma patients. In Burkitt lymphoma, hsa-miR197 and miR510 were most frequently assessed human micro RNAs. Also, miR-BART6-3P and miR-BART17-5P were the most frequent viral micro RNAs in Burkitt lymphoma. Other human important micro RNAs were hsa-miR155 (in Diffuse large B cell lymphoma (DLBCL)), hsa-miR145 (in Nasal natural killer T cell lymphoma (NNKTCL)), miR-96, miR-128a, miR-128b, miR-129, and miR-205 (in Classic Hodgkin lymphoma (CHL)), miR-21, miR-142-3P, miR-126, miR-451 and miR-494-3P (in Nasal natural killer cell lymphoma (NNKCL)). Also, viral assessed micro RNAs were miR-BART1-5P (in DLBCL and NNKTCL), miR-BART-5 (in CHL), and EBV-miR-BART20-5P (in NNKCL). In conclusion, it could be suggested that EBV-encoded-microRNAs and EBV-induced cellular-microRNAs can be utilized as helpful factors for different types of lymphoma diagnoses or prognostic factors. Moreover, the mentioned microRNAs can also be promising therapeutic targets and can be used to modulate the oncogenes.


Assuntos
Infecções por Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/metabolismo , Linfoma/diagnóstico , Linfoma/metabolismo , MicroRNAs/metabolismo , RNA Viral/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Progressão da Doença , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4/genética , Humanos , Linfoma/genética , Linfoma/virologia , MicroRNAs/genética , Prognóstico , RNA Viral/genética
8.
Exp Mol Pathol ; 119: 104606, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33493455

RESUMO

As a malignant tumor originating from the lymphoid hematopoietic tissues, lymphoma has an increased incidence in recent years and has ranked among the top ten malignant tumors in the world. But until now, due to the multiple pathological subtypes and the unclear molecular mechanism, it's still difficult to make rapid diagnosis and accurate prognosis assessment for lymphoma patients. Recently, the development of high-throughput gene sequencing technology has provided the possibility to solve these clinical problems. This technology has realized large-scale screening of specific markers for lymphoma at the molecular biology level, followed by discovery of prognostic indicators and biological targets for new drug research. In this paper, we summarize the results of large-scale high-throughput gene sequencing research, and introduce the genetic changes associated with occurrence and prognosis of lymphomas with different pathological subtypes, hoping to further promote the application of this technology in clinical research of lymphoma.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Linfoma/genética , Humanos , Mutação/genética
10.
Nat Commun ; 11(1): 3520, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665551

RESUMO

PRDM (PRDI-BF1 and RIZ homology domain containing) family members are sequence-specific transcriptional regulators involved in cell identity and fate determination, often dysregulated in cancer. The PRDM15 gene is of particular interest, given its low expression in adult tissues and its overexpression in B-cell lymphomas. Despite its well characterized role in stem cell biology and during early development, the role of PRDM15 in cancer remains obscure. Herein, we demonstrate that while PRDM15 is largely dispensable for mouse adult somatic cell homeostasis in vivo, it plays a critical role in B-cell lymphomagenesis. Mechanistically, PRDM15 regulates a transcriptional program that sustains the activity of the PI3K/AKT/mTOR pathway and glycolysis in B-cell lymphomas. Abrogation of PRDM15 induces a metabolic crisis and selective death of lymphoma cells. Collectively, our data demonstrate that PRDM15 fuels the metabolic requirement of B-cell lymphomas and validate it as an attractive and previously unrecognized target in oncology.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Western Blotting , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Imunoprecipitação da Cromatina , Biologia Computacional , Proteínas de Ligação a DNA/genética , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Humanos , Linfoma/genética , Linfoma/metabolismo , Camundongos , Camundongos SCID , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Distribuição Aleatória , Fatores de Transcrição/genética , Transcriptoma/genética
11.
Ann Hematol ; 99(10): 2231-2242, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32621182

RESUMO

Long non-coding RNAs (lncRNAs) have an established role in cell biology. Among their functions is the regulation of hematopoiesis. They characterize the different stages of hematopoiesis in a more lineage-restricted expression pattern than coding mRNAs. They affect hematopoietic stem cell renewal, proliferation, and differentiation of committed progenitors by interacting with master regulators transcription factors. Among these transcription factors, MYC has a prominent role. Similar to MYC's transcriptional activation/amplification of protein coding genes, MYC also regulates lncRNAs' expression profile, while it is also regulated by lncRNAs. Both myeloid and lymphoid malignancies are prone to the association of MYC with lncRNAs. Such interaction inhibits apoptosis, enhances cell proliferation, deregulates metabolism, and promotes genomic instability and resistance to treatment. In this review, we discuss the recent findings that encompass the crosstalk between lncRNAs and describe the pathways that very probably have a pathogenetic role in both acute and chronic hematologic malignancies.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hematológicas/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas c-myc/fisiologia , RNA Longo não Codificante/genética , RNA Neoplásico/genética , Autorrenovação Celular/genética , Genes myc , Hematopoese/genética , Humanos , Leucemia/genética , Linfócitos/metabolismo , Linfócitos/patologia , Linfoma/genética , Mieloma Múltiplo/genética , Células Mieloides/metabolismo , Células Mieloides/patologia , Nicho de Células-Tronco
12.
Medicine (Baltimore) ; 99(24): e20733, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541525

RESUMO

INTRODUCTION: To investigate the gene rearrangement and mutation of lymphoma biomarkers including (Immunoglobulin H (IgH), Immunoglobulin kappa (IGK), Immunoglobulin lambda (IGL), and TCR) in the lymphoma diagnosis. METHODS AND ANALYSIS: Paraffin tissue samples from 240 cases diagnosed as suspected lymphoma in the department of pathology, Deyang City People's Hospital from June 2020 to June 2021 will be enrolled. Deoxyribonucleic acid extraction and Polymerase Chain Reaction (PCR) amplification will be performed in these paraffin tissue samples. Immunoglobulin and T cell receptor (TCR) rearrangement will be analyzed by hetero-double chain gel electrophoresis and BioMed-2 standardized immunoglobulin gene rearrangement detection system. In this study protocol IGH gene rearrangement, IGK gene rearrangement, both IGH and IGL gene rearrangement, both IGH and IGK gene rearrangement, both IGK and IGL gene rearrangement, both IGH, IGK and IGL gene rearrangement, TCR gene rearrangement and positive Ig/TCR rearrangement will be analyzed. DISCUSSION: In this study, we will use B and T cell lymphoma analysis focusing on IgH, IGK, IGL, and TCR gene rearrangement, so as to provide early guidance for the diagnosis of lymphoma. Second generation sequencing technology is helpful in the differential diagnosis of lymphoma. TRIAL REGISTRATION: Chinese Clinical trial registry: ChiCTR2000032366.


Assuntos
Rearranjo Gênico , Linfoma/genética , Mutação , Estudos Observacionais como Assunto/métodos , Projetos de Pesquisa , Humanos , Estudos Prospectivos
13.
Mol Genet Genomics ; 295(5): 1197-1209, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32500265

RESUMO

Growing evidence indicates that the development and progression of multiple complex diseases are influenced by microRNA (miRNA). Identifying more miRNAs as biomarkers for clinical diagnosis, treatment and prognosis is vital to promote the development of bioinformatics and medicine. Considering that the traditional biological experimental methods are generally time-consuming and expensive, high-efficient computational methods are encouraged to uncover potential disease-related miRNAs. In this paper, FCGCNMDA is presented to predict latent miRNA-disease associations by utilizing fully connected graph convolutional networks. Specially, our method first constructs a fully connected graph in which edge weights represent correlation coefficient between any two pairs of miRNA-disease pair, and then feeds this fully connected graph along with miRNA-disease pairs feature matrix into a two-layer graph convolutional networks (GCN) for training. At last, we utilize the trained network to predict the scores for unknown miRNA-disease pairs. As a result, FCGCNMDA achieves AUC value of [Formula: see text] and AUPRC value of [Formula: see text] in HMDD v2.0 based on five-fold cross validation. Moreover, case studies on Lymphoma, Breast Neoplasms and Prostate Neoplasms shown that 98%, 98%, 98% of the top 50 selected miRNAs were validated by recent experimental evidence. From above results, we can deduce that FCGCNMDA can be regarded as reliable method for potential miRNA-disease associations prediction.


Assuntos
Neoplasias da Mama/genética , Biologia Computacional/métodos , Estudos de Associação Genética/métodos , Linfoma/genética , MicroRNAs/genética , Neoplasias da Próstata/genética , Algoritmos , Área Sob a Curva , Aprendizado Profundo , Diagnóstico Precoce , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Masculino , Prognóstico
14.
Proc Natl Acad Sci U S A ; 117(24): 13740-13749, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32471947

RESUMO

Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of a T cell neoplasm and several inflammatory diseases. A viral gene, HTLV-1 bZIP factor (HBZ), induces pathogenic Foxp3-expressing T cells and triggers systemic inflammation and T cell lymphoma in transgenic mice, indicating its significance in HTLV-1-associated diseases. Here we show that, unexpectedly, a proinflammatory cytokine, IL-6, counteracts HBZ-mediated pathogenesis. Loss of IL-6 accelerates inflammation and lymphomagenesis in HBZ transgenic mice. IL-6 innately inhibits regulatory T cell differentiation, suggesting that IL-6 functions as a suppressor against HBZ-associated complications. HBZ up-regulates expression of the immunosuppressive cytokine IL-10. IL-10 promotes T cell proliferation only in the presence of HBZ. As a mechanism of growth promotion by IL-10, HBZ interacts with STAT1 and STAT3 and modulates the IL-10/JAK/STAT signaling pathway. These findings suggest that HTLV-1 promotes the proliferation of infected T cells by hijacking the machinery of regulatory T cell differentiation. IL-10 induced by HBZ likely suppresses the host immune response and concurrently promotes the proliferation of HTLV-1 infected T cells.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Interleucina-6/imunologia , Linfoma/virologia , Proteínas dos Retroviridae/imunologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Diferenciação Celular , Proliferação de Células , Infecções por HTLV-I/genética , Infecções por HTLV-I/patologia , Infecções por HTLV-I/virologia , Interações Hospedeiro-Patógeno , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Linfoma/genética , Linfoma/imunologia , Linfoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Retroviridae/genética , Linfócitos T Reguladores/imunologia
15.
Nat Commun ; 11(1): 2319, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385234

RESUMO

Bruton's tyrosine kinase (Btk) is critical for B-cell maturation and activation. Btk loss-of-function mutations cause human X-linked agammaglobulinemia (XLA). In contrast, Btk signaling sustains growth of several B-cell neoplasms which may be treated with tyrosine kinase inhibitors (TKIs). Here, we uncovered the structural mechanism by which certain XLA mutations in the SH2 domain strongly perturb Btk activation. Using a combination of molecular dynamics (MD) simulations and small-angle X-ray scattering (SAXS), we discovered an allosteric interface between the SH2 and kinase domain required for Btk activation and to which multiple XLA mutations map. As allosteric interactions provide unique targeting opportunities, we developed an engineered repebody protein binding to the SH2 domain and able to disrupt the SH2-kinase interaction. The repebody prevents activation of wild-type and TKI-resistant Btk, inhibiting Btk-dependent signaling and proliferation of malignant B-cells. Therefore, the SH2-kinase interface is critical for Btk activation and a targetable site for allosteric inhibition.


Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Cristalografia por Raios X/métodos , Linfoma/metabolismo , Tirosina Quinase da Agamaglobulinemia/genética , Western Blotting , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Dicroísmo Circular , Citometria de Fluxo , Células HEK293 , Humanos , Immunoblotting , Imunoprecipitação , Linfoma/genética , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Mutação/genética
16.
Clin Sci (Lond) ; 134(10): 1151-1166, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32420596

RESUMO

A percentage of celiac disease (CD) patients develop refractory type-2 disease (RCD2), a condition associated with increased risk of enteropathy-associated T-cell-lymphoma (EATL) and without therapeutic option. Therefore, we profiled the miRNome in series of peripheral T-cell lymphomas (PTCLs), CD, RCD1 or 2 and in the murine interleukin-15 (IL15)-transgenic (TG) model of RCD. The transcriptome was analyzed in 18 intestinal T-cell lymphomas (ITLs). Bioinformatics pipelines provided significant microRNA (miRNA) lists and predicted targets that were confirmed in a second set of patients. Our data show that ITLs have a unique miRNA profile with respect to other PTCLs. The c-MYC regulated miR-17/92 cluster distinguishes monomorphic epitheliotropic ITL (MEITL) from EATL and prognosticates EATL outcome. These miRNAs are decreased in IL15-TG mice upon Janus kinase (JAK) inhibition. The random forest algorithm identified a signature of 38 classifier miRNAs, among which, the miR-200 and miR-192/215 families were progressively lost in RCD2 and ITL-CD, whereas miR-17/92 and C19MC miRNAs were up-regulated. Accordingly, SMAD3, MDM2, c-Myc and activated-STAT3 were increased in RCD2 and EATL tissues while JAK inhibition in IL15-TG mice restored their levels to baseline. Our data suggest that miRNAs circuit supports activation of STAT3 and c-Myc oncogenic signaling in RCD2, thus contributing to lymphomagenesis. This novel understanding might pave the way to personalized medicine approaches for RCD and EATL.


Assuntos
Carcinogênese/genética , Doença Celíaca/genética , Regulação Neoplásica da Expressão Gênica , Linfoma/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Algoritmos , Animais , Biomarcadores Tumorais/metabolismo , Feminino , Intestinos/patologia , Linfoma/patologia , Masculino , Camundongos Transgênicos , MicroRNAs/metabolismo , Modelos Biológicos , Prognóstico , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Smad3/metabolismo , Regulação para Cima/genética
17.
Sci Rep ; 10(1): 8705, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32457435

RESUMO

With critical roles in regulating gene expression, miRNAs are strongly implicated in the pathophysiology of many complex diseases. Experimental methods to determine disease related miRNAs are time consuming and costly. Computationally predicting miRNA-disease associations has potential applications in finding miRNA therapeutic pathways and in understanding the role of miRNAs in disease-disease relationships. In this study, we propose the MiRNA-disease Association Prediction (MAP) method, an in-silico method to predict and prioritize miRNA-disease associations. The MAP method applies a network diffusion approach, starting from the known disease genes in a heterogenous network constructed from miRNA-gene associations, protein-protein interactions, and gene-disease associations. Validation using experimental data on miRNA-disease associations demonstrated superior performance to two current state-of-the-art methods, with areas under the ROC curve all over 0.8 for four types of cancer. MAP is successfully applied to predict differential miRNA expression in four cancer types. Most strikingly, disease-disease relationships in terms of shared miRNAs revealed hidden disease subtyping comparable to that of previous work on shared genes between diseases, with applications for multi-omics characterization of disease relationships.


Assuntos
Biologia Computacional/métodos , Doença/genética , MicroRNAs/metabolismo , Algoritmos , Área Sob a Curva , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Bases de Dados Genéticas , Humanos , Linfoma/genética , Linfoma/patologia , MicroRNAs/genética , Neoplasias/genética , Neoplasias/patologia , Curva ROC
18.
Am J Pathol ; 190(3): 602-613, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32113662

RESUMO

Casitas B-lineage lymphoma (c-Cbl) is a recently identified ubiquitin ligase of nuclear ß-catenin and a suppressor of colorectal cancer (CRC) growth in cell culture and mouse tumor xenografts. We hypothesized that reduction in c-Cbl in colonic epithelium is likely to increase the levels of nuclear ß-catenin in the intestinal crypt, augmenting CRC tumorigenesis in an adenomatous polyposis coli (APCΔ14/+) mouse model. Haploinsufficient c-Cbl mice (APCΔ14/+ c-Cbl+/-) displayed a significant (threefold) increase in atypical hyperplasia and adenocarcinomas in the small and large intestines; however, no differences were noted in the adenoma frequency. In contrast to the APCΔ14/+ c-Cbl+/+ mice, APCΔ14/+ c-Cbl+/- crypts showed nuclear ß-catenin throughout the length of the crypts and up-regulation of Axin2, a canonical Wnt target gene, and SRY-box transcription factor 9, a marker of intestinal stem cells. In contrast, haploinsufficiency of c-Cbl+/- alone was insufficient to induce tumorigenesis regardless of an increase in the number of intestinal epithelial cells with nuclear ß-catenin and SRY-box transcription factor 9 in APC+/+ c-Cbl+/- mice. This study demonstrates that haploinsufficiency of c-Cbl results in Wnt hyperactivation in intestinal crypts and accelerates CRC progression to adenocarcinoma in the milieu of APCΔ14/+, a phenomenon not found with wild-type APC. While emphasizing the role of APC as a gatekeeper in CRC, this study also demonstrates that combined partial loss of c-Cbl and inactivation of APC significantly contribute to CRC tumorigenesis.


Assuntos
Adenocarcinoma/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Neoplasias do Colo/genética , Neoplasias Colorretais/genética , Haploinsuficiência , Linfoma/genética , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Adenocarcinoma/patologia , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Carcinogênese , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Linfoma/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-cbl/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
19.
J Virol ; 94(10)2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32132242

RESUMO

Epstein-Barr virus (EBV) causes B cell lymphomas and transforms B cells in vitro The EBV protein EBNA3A collaborates with EBNA3C to repress p16 expression and is required for efficient transformation in vitro An EBNA3A deletion mutant EBV strain was recently reported to establish latency in humanized mice but not cause tumors. Here, we compare the phenotypes of an EBNA3A mutant EBV (Δ3A) and wild-type (WT) EBV in a cord blood-humanized (CBH) mouse model. The hypomorphic Δ3A mutant, in which a stop codon is inserted downstream from the first ATG and the open reading frame is disrupted by a 1-bp insertion, expresses very small amounts of EBNA3A using an alternative ATG at residue 15. Δ3A caused B cell lymphomas at rates similar to their induction by WT EBV but with delayed onset. Δ3A and WT tumors expressed equivalent levels of EBNA2 and p16, but Δ3A tumors in some cases had reduced LMP1. Like the WT EBV tumors, Δ3A lymphomas were oligoclonal/monoclonal, with typically one dominant IGHV gene being expressed. Transcriptome sequencing (RNA-seq) analysis revealed small but consistent gene expression differences involving multiple cellular genes in the WT EBV- versus Δ3A-infected tumors and increased expression of genes associated with T cells, suggesting increased T cell infiltration of tumors. Consistent with an impact of EBNA3A on immune function, we found that the expression of CLEC2D, a receptor that has previously been shown to influence responses of T and NK cells, was markedly diminished in cells infected with EBNA3A mutant virus. Together, these studies suggest that EBNA3A contributes to efficient EBV-induced lymphomagenesis in CBH mice.IMPORTANCE The EBV protein EBNA3A is expressed in latently infected B cells and is important for efficient EBV-induced transformation of B cells in vitro In this study, we used a cord blood-humanized mouse model to compare the phenotypes of an EBNA3A hypomorph mutant virus (Δ3A) and wild-type EBV. The Δ3A virus caused lymphomas with delayed onset compared to the onset of those caused by WT EBV, although the tumors occurred at a similar rate. The WT EBV and EBNA3A mutant tumors expressed similar levels of the EBV protein EBNA2 and cellular protein p16, but in some cases, Δ3A tumors had less LMP1. Our analysis suggested that Δ3A-infected tumors have elevated T cell infiltrates and decreased expression of the CLEC2D receptor, which may point to potential novel roles of EBNA3A in T cell and NK cell responses to EBV-infected tumors.


Assuntos
Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Sangue Fetal/metabolismo , Herpesvirus Humano 4/genética , Linfoma/virologia , Animais , Linfócitos B/virologia , Transformação Celular Viral , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Herpesvirus Humano 4/fisiologia , Humanos , Células Matadoras Naturais/imunologia , Linfoma/genética , Linfoma/patologia , Linfoma de Células B , Camundongos , Mutagênese Sítio-Dirigida , Análise de Sequência de RNA , Deleção de Sequência , Linfócitos T/imunologia , Proteínas Virais/genética , Proteínas Virais/metabolismo , Latência Viral/genética
20.
Hematol Oncol ; 38(4): 432-438, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32073154

RESUMO

The meeting, which brought together leading scientists and clinicians in the field of leukemia and lymphoma, was held at the new headquarters of the Josep Carreras Leukaemia Research Institute (IJC) in Badalona, Catalonia, Spain, September 19-20, 2019. Its purpose was to highlight the latest advances in our understanding of the molecular mechanisms driving blood cancers, and to discuss how this knowledge can be translated into an improved management of the disease. Special emphasis was placed on the role of genetic and epigenetic heterogeneity, and the exploitation of epigenetic regulation for developing biomarkers and novel treatment approaches.


Assuntos
Metilação de DNA , Epigênese Genética , Genômica , Leucemia/genética , Linfoma/genética , Congressos como Assunto , Humanos , Leucemia/diagnóstico , Leucemia/terapia , Linfoma/diagnóstico , Linfoma/terapia
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