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1.
NAR Cancer ; 4(4): zcac041, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36518527

RESUMO

A significant proportion of infant B-cell acute lymphoblastic leukemia (B-ALL) patients remains with a dismal prognosis due to yet undetermined mechanisms. We performed a comprehensive multicohort analysis of gene expression, gene fusions, and RNA splicing alterations to uncover molecular signatures potentially linked to the observed poor outcome. We identified 87 fusions with significant allele frequency across patients and shared functional impacts, suggesting common mechanisms across fusions. We further identified a gene expression signature that predicts high risk independently of the gene fusion background and includes the upregulation of the splicing factor SRRM1. Experiments in B-ALL cell lines provided further evidence for the role of SRRM1 on cell survival, proliferation, and invasion. Supplementary analysis revealed that SRRM1 potentially modulates splicing events associated with poor outcomes through protein-protein interactions with other splicing factors. Our findings reveal a potential convergent mechanism of aberrant RNA processing that sustains a malignant phenotype independently of the underlying gene fusion and that could potentially complement current clinical strategies in infant B-ALL.

2.
Nat Med ; 28(8): 1662-1671, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35953718

RESUMO

Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)high-B cell receptor (BCR)low-signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT.


Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Transformação Celular Neoplásica/genética , Progressão da Doença , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia
3.
J Dermatol Sci ; 89(2): 120-126, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29239787

RESUMO

BACKGROUND: Psoriasis is an immune-mediated, inflammatory and hyperproliferative disease of the skin and joints. The cause of psoriasis is still unknown. The fundamental feature of the disease is the hyperproliferation of keratinocytes and the recruitment of cells from the immune system in the region of the affected skin, which leads to deregulation of many well-known gene expressions. OBJECTIVE: Based on data mining and bioinformatic scripting, here we show a new dimension of the effect of psoriasis at the genomic level. METHODS: Using our own pipeline of scripts in Perl and MySql and based on the freely available NCBI Gene Expression Omnibus (GEO) database: DataSet Record GDS4602 (Series GSE13355), we explore the extent of the effect of psoriasis on gene expression in the affected tissue. RESULTS: We give greater insight into the effects of psoriasis on the up-regulation of some genes in the cell cycle (CCNB1, CCNA2, CCNE2, CDK1) or the dynamin system (GBPs, MXs, MFN1), as well as the down-regulation of typical antioxidant genes (catalase, CAT; superoxide dismutases, SOD1-3; and glutathione reductase, GSR). We also provide a complete list of the human genes and how they respond in a state of psoriasis. CONCLUSION: Our results show that psoriasis affects all chromosomes and many biological functions. If we further consider the stable and mitotically inheritable character of the psoriasis phenotype, and the influence of environmental factors, then it seems that psoriasis has an epigenetic origin. This fit well with the strong hereditary character of the disease as well as its complex genetic background.


Assuntos
Proliferação de Células/genética , Biologia Computacional/métodos , Queratinócitos/metabolismo , Psoríase/genética , Pele/metabolismo , Ciclo Celular/genética , Cromossomos Humanos/genética , Mineração de Dados/métodos , Conjuntos de Dados como Assunto , Regulação para Baixo , Epigênese Genética/genética , Humanos , Psoríase/fisiopatologia , Pele/citologia , Pele/fisiopatologia , Regulação para Cima
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