RESUMEN
In chronic lymphocytic leukemia (CLL), the mechanisms controlling cell growth and proliferation in the presence of NOTCH1 mutations remain largely unexplored. By performing a gene expression profile of NOTCH1-mutated (NOTCH1-mut) versus NOTCH1 wild-type CLL, we identified a gene signature of NOTCH1-mut CLL characterized by the upregulation of genes related to ribosome biogenesis, such as nucleophosmin 1 (NPM1) and ribosomal proteins (RNPs). Activation of NOTCH1 signaling by ethylenediaminetetraacetic acid or by coculture with JAGGED1-expressing stromal cells increased NPM1 expression, and inhibition of NOTCH1 signaling by either NOTCH1-specific small interfering RNA (siRNA) or γ-secretase inhibitor reduced NPM1 expression. Bioinformatic analyses and in vitro activation/inhibition of NOTCH1 signaling suggested a role of MYC as a mediator of NOTCH1 effects over NPM1 and RNP expression in NOTCH1-mut CLL. Chromatin immunoprecipitation experiments performed on NOTCH1 intracellular domain (NICD)-transfected CLL-like cells showed the direct binding of NOTCH1 to the MYC promoter, and transfection with MYC-specific siRNA reduced NPM1 expression. In turn, NPM1 determined a proliferation advantage of CLL-like cells, as demonstrated by NPM1-specific siRNA transfection. In conclusion, NOTCH1 mutations in CLL are associated with the overexpression of MYC and MYC-related genes involved in protein biosynthesis including NPM1, which are allegedly responsible for cell growth and/or proliferation advantages of NOTCH1-mut CLL.
Asunto(s)
Genes myc , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Proteínas Nucleares/metabolismo , Receptor Notch1/genética , Ribosomas/metabolismo , Proliferación Celular , Técnicas de Cocultivo , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Nucleofosmina , Receptor Notch1/metabolismo , Transducción de Señal , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has achieved an 80% cure rate as a result of a risk-adapted therapy largely based on minimal residual disease (MRD) monitoring. However, relapse is still the most frequent adverse event, occurring mainly in the patients with intermediate MRD levels (intermediate risk, IR), emphasizing the need for new prognostic markers. We analyzed the prognostic impact of cytokine receptor-like factor 2 (CRLF2) over-expression and P2RY8-CRLF2 fusion in 464 BCP-ALL patients (not affected by Down syndrome and BCR-ABL negative) enrolled in the AIEOP-BFM ALL2000 study in Italy. In 22/464 (4.7%) samples, RQ-PCR showed CRLF2 over-expression (≥20 times higher than the overall median). P2RY8-CRLF2 fusion was detected in 22/365 (6%) cases, with 10/22 cases also showing CRLF2 over-expression. P2RY8-CRLF2 fusion was the most relevant prognostic factor independent of CRLF2 over-expression with a threefold increase in risk of relapse. Significantly, the cumulative incidence of relapse of the P2RY8-CRLF2 + patients in the IR group was high (61.1% ± 12.9 vs 17.6% ± 2.6, P<0.0001), similar to high-risk patients in AIEOP-BFM ALL2000 study. These results were confirmed in a cohort of patients treated in Germany. In conclusion, P2RY8-CRLF2 identifies a subset of BCP-ALL patients currently stratified as IR that could be considered for treatment intensification.
Asunto(s)
Fusión Génica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Receptores de Citocinas/fisiología , Receptores Purinérgicos P2/genética , Humanos , Pronóstico , Modelos de Riesgos Proporcionales , Receptores de Citocinas/genética , Recurrencia , Factores de RiesgoRESUMEN
Acreditação hospitalar combina segurança com ética profissional, responsabilidade e qualidade do atendimento, melhorando o geren¬ciamento do serviço, da qualidade da assistência ao paciente. Este estudo descritivo, exploratório, documental, realizado em instituição pública de cardiologia, objetivou identificar dificuldades para certificação de qualidade de nível I, no olhar dos enfermeiros e propor medidas de gerenciamento. A coleta foi realizada, utilizando-se de documentos da acreditação hospitalar. As dificuldades encontradas foram estruturais e operacionais; de organização de processos e gestão de recursos humanos; de evidenciar programa de educação e treinamento continuado institucional e avaliação de efetividade; de interação sistêmica dos componentes, atividades e serviços de apoio técnico à organização; de planejamento, aquisição, armazenamento, rastreabilidade e disponibilização de recursos materiais e a falta de evidencias de documentações atualizadas, disponíveis, aplicadas e sistematizadas. Frente ao diagnóstico, ações estratégicas para resolu¬ção do problema e participação do enfermeiro foram desenvolvidas, junto às lideranças e administradores.
