RESUMEN
The mechanisms underlying human natural killer (NK) cell phenotypic and functional heterogeneity are unknown. Here, we describe the emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins after human cytomegalovirus (HCMV) infection. The absence of B and myeloid cell-related signaling protein expression in these NK cell subsets correlated with promoter DNA hypermethylation. Genome-wide DNA methylation patterns were strikingly similar between HCMV-associated adaptive NK cells and cytotoxic effector T cells but differed from those of canonical NK cells. Functional interrogation demonstrated altered cytokine responsiveness in adaptive NK cells that was linked to reduced expression of the transcription factor PLZF. Furthermore, subsets of adaptive NK cells demonstrated significantly reduced functional responses to activated autologous T cells. The present results uncover a spectrum of epigenetically unique adaptive NK cell subsets that diversify in response to viral infection and have distinct functional capabilities compared to canonical NK cell subsets.
Asunto(s)
Anticuerpos/inmunología , Infecciones por Citomegalovirus/genética , Epigénesis Genética/inmunología , Células Asesinas Naturales/inmunología , Factores de Transcripción de Tipo Kruppel/inmunología , Linfocitos T Citotóxicos/inmunología , Inmunidad Adaptativa , Proliferación Celular , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/patología , Infecciones por Citomegalovirus/virología , Metilación de ADN , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/inmunología , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/inmunología , Células Asesinas Naturales/clasificación , Células Asesinas Naturales/patología , Células Asesinas Naturales/virología , Factores de Transcripción de Tipo Kruppel/deficiencia , Factores de Transcripción de Tipo Kruppel/genética , Análisis por Micromatrices , Subfamília C de Receptores Similares a Lectina de Células NK/deficiencia , Subfamília C de Receptores Similares a Lectina de Células NK/genética , Subfamília C de Receptores Similares a Lectina de Células NK/inmunología , Regiones Promotoras Genéticas , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Proteínas Tirosina Quinasas/deficiencia , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/inmunología , Receptores de IgG/deficiencia , Receptores de IgG/genética , Receptores de IgG/inmunología , Transducción de Señal , Quinasa Syk , Linfocitos T Citotóxicos/patología , Linfocitos T Citotóxicos/virología , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Factores de Transcripción/inmunologíaRESUMEN
BACKGROUND: For pediatric ALL patients that relapse or respond poorly to conventional chemotherapy treatment, HSCT is one treatment option. Still, relapse occurs in 30% of the children after HSCT. Mutations in the tumor suppressor gene TP53 which can lead to an altered p53 protein expression are rare at time of diagnosis of ALL, yet occur more frequent at relapse indicating a more aggressive disease. Our aim was to evaluate if alterations in the expression of the tumor suppressor protein p53 signaled a relapse in pediatric ALL patients post-HSCT and could guide for preemptive immunotherapy. PROCEDURE: Paraffin-embedded bone marrow samples from 46 children diagnosed with ALL between 1997 and 2010, and transplanted at Karolinska University Hospital, were analyzed for p53 by IHC. Samples were analyzed independently at diagnosis, before HSCT, and after HSCT 0-3 months, 3-6 months, and 6-12 months. RESULT: Strong expression of p53 in the bone marrow at 0-3-months after HSCT was associated with increased risk of relapse, odds ratio 2.63 (confidence interval 1.08-6.40) P = 0.033. CONCLUSION: Evaluation of p53 protein expression in bone marrow from pediatric ALL patients that undergo HSCT may be a potential, additional prognostic marker for predicting relapse after HSCT.
Asunto(s)
Médula Ósea/metabolismo , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Adolescente , Niño , Preescolar , Femenino , Regulación Leucémica de la Expresión Génica , Humanos , Inmunohistoquímica , Inmunoterapia , Lactante , Recién Nacido , Masculino , Mutación , Oportunidad Relativa , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pronóstico , Recurrencia , Riesgo , SueciaRESUMEN
SCL/TAL1 interrupting locus (STIL)-T-cell acute leukaemia (TAL1) fusion genes are present in approximately 11-27% of children with paediatric T-cell acute lymphoblastic leukaemia (T-ALL), but the developmental timing of the rearrangement is still unknown. To investigate whether the fusion gene can be detected in neonatal blood spots (NBSs) from paediatric patients diagnosed with T-cell ALL, we analysed DNA from 38 paediatric patients with T-ALL by nested polymerase chain reaction and electrophoresis. The STIL-TAL1 fusion gene was not detected in NBSs from any of the 38 patients with T-ALL, suggesting that STIL-TAL1 fusion genes are most probably postnatal events in paediatric T-ALL.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
Dysregulation of genes involved in the cell cycle such as TP53, P21, P16, and PTEN plays a key role in oncogenesis. We have earlier reported increased expression of the TP53 encoded protein p53, in bone marrow samples from pediatric patients with more aggressive, rare chronic myeloid malignancies. The aim of this study was to investigate protein expression of p53, p21, p16, and PTEN before and after HSCT in pediatric patients with AML and evaluate whether any potential alterations could predict relapse after HSCT. Paraffin-embedded bone marrow samples from 34 pediatric patients with AML were collected retrospectively from time of diagnosis as well as pre- and post-HSCT. IHC was performed on tissue microarrays with antibodies against p53, p21, p16, and PTEN. Study material was analyzed by independent t-tests and nonlinear regression. t-Tests showed a statistical significant difference in p53 (p = 0.010) with overexpression in the group of patients who relapsed compared to the relapse-free patients at >3-6 months post-HSCT. Analysis of p53 protein expression by IHC may be a potential predictor for relapse after HSCT in children with AML.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Proteína p53 Supresora de Tumor/metabolismo , Adolescente , Biomarcadores/metabolismo , Médula Ósea/metabolismo , Niño , Preescolar , Femenino , Humanos , Lactante , Leucemia Mieloide Aguda/metabolismo , Modelos Logísticos , Masculino , Recurrencia , Estudios Retrospectivos , Análisis de Matrices Tisulares , Trasplante Homólogo , Resultado del TratamientoRESUMEN
BACKGROUND: Alterations in the tumor suppressor gene TP53 have been associated with poor outcome in adult hematological malignancies. We have earlier reported an increased expression of the TP53 encoded protein p53, in bone marrow samples from pediatric patients with aggressive leukemia. Our aim was now to evaluate p53 protein expression at different time points before and after hematopoietic stem cell transplantation (HSCT) as a predictor of relapse in a group of children diagnosed with MDS, JMML and CML, and also investigate if potential alterations in expression could be correlated to mutations in TP53. PROCEDURE: Paraffin embedded bone marrow samples from 33 pediatric patients diagnosed with MDS, JMML and CML between 1997 and 2010 were collected retrospectively from time of diagnosis and pre and post HSCT. Immunohistochemistry (IHC) was performed on tissue microarrays (TMA) with antibodies to p53 and p21. DNA sequencing of exon 2-11 of TP53 was performed in 7 patients with JMML and 5 patients with MDS. RESULTS: Elevated p53 protein expression at diagnosis predicted for relapse, odds ratio (OR) 1.19 (95% CI: 1.02-1.40, p = .028). Sequencing of TP53 did not reveal any mutations in the 12 patients analyzed and p53 expression correlated positively to p21 expression indicating a functional p53/p21 protein pathway. CONCLUSION: Elevated p53 protein expression at diagnosis may be an indicator of relapse in children with MDS, JMML and CML.