RESUMEN
The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex is one of the most remarkably altered epigenetic regulators in cancer. Pathogenic mutations in genes encoding SWI/SNF-related proteins have been recently described in many solid tumors, including rare and aggressive malignancies with rhabdoid features with no standard therapies in advanced or metastatic settings. In recent years, clinical trials with targeted drugs aimed at restoring its function have shown discouraging results. However, preclinical data have found an association between these epigenetic alterations and response to immune therapy. Thus, the rationale for immunotherapy strategies in SWI/SNF complex alteration-related tumors is strong. Here, we review the SWI/SNF complex and how its dysfunction drives the oncogenesis of rhabdoid tumors and the proposed strategies to revert this alteration and promising novel therapeutic approaches, including immune checkpoint inhibition and adoptive cell therapy.
Asunto(s)
Proteínas de Unión al ADN , Tumor Rabdoide , Humanos , Proteínas de Unión al ADN/genética , Inmunoterapia Adoptiva , Proteínas Nucleares/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Tumor Rabdoide/genética , Tumor Rabdoide/terapia , Tumor Rabdoide/patologíaRESUMEN
PURPOSE: Glucocorticoids are part of the therapeutic armamentarium of chronic lymphocytic leukemia (CLL) where it has been suggested that cells with unmutated IGHV genes exhibit higher sensitivity. The mechanisms by which glucocorticoids are active in CLL are not well elucidated. We aimed to ascertain the activity of dexamethasone in CLL cells according to prognosis and to identify the molecular mechanisms that are influencing the response to this drug. EXPERIMENTAL DESIGN: Sensitivity to dexamethasone was analyzed ex vivo in 50 CLL and compared according to IGHV mutational status and/or ZAP-70 expression. The response was further compared by gene expression profiling (GEP) of selected cases. Expression of genes of interest was validated by quantitative reverse transcriptase PCR. RESULTS: Response to dexamethasone was higher in cases with unmutated IGHV/high ZAP-70 expression, and the levels of induction of the pro-apoptotic Bim protein correlated with the degree of cell death. GEP analysis showed few genes differentially expressed after dexamethasone treatment between mutated and unmutated cases. However, functional annotation analysis showed that unmutated cases had significant enrichment in terms related to apoptosis. Specific analysis of genes of interest conducted in a large series disclosed that in unmutated IGHV cells, FKBP5 expression was higher at baseline and after dexamethasone exposure and that GILZ was more induced by dexamethasone treatment in these cases. CONCLUSIONS: Unmutated IGHV/high ZAP-70 CLL cells exhibit better response to dexamethasone treatment, which is accompanied by a differential expression of genes involved in the glucocorticoid receptor pathway and by an increased induction of genes related to apoptosis.
Asunto(s)
Apoptosis , Regulación Leucémica de la Expresión Génica , Genes de las Cadenas Pesadas de las Inmunoglobulinas/genética , Leucemia Linfocítica Crónica de Células B/genética , Transcriptoma , Proteína Tirosina Quinasa ZAP-70/genética , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/efectos de los fármacos , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/genética , Proteína 11 Similar a Bcl2 , Análisis por Conglomerados , Dexametasona/farmacología , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas/genética , Interferencia de ARN , Proteínas de Unión a Tacrolimus/genética , Proteínas de Unión a Tacrolimus/metabolismo , Factores de Transcripción/genéticaRESUMEN
ZAP-70 in chronic lymphocytic leukemia (CLL) has been associated with enhanced B-cell receptor (BCR) signaling, survival, and migration. We investigated whether ZAP-70 can directly govern migration and the underlying mechanisms. In the ZAP-70 stably transfected Ramos cell line, IgM stimulation, but no IgD, enhanced phosphorylation of ERK1/2, Akt and Syk, and delayed IgM and CD79b internalization. In contrast, in the Raji cell line, where ZAP-70 was constitutively phosphorylated, ERK1/2, but not Akt, was phosphorylated, suggesting that MAPK pathway mediates ZAP-70 effects. BCR stimulation modulated the expression of CCR7, CXCR4, CXCR5, CD44, CD49d, and CD62L, which were up-regulated in ZAP-70-positive CLL primary subclones. The most dramatic change after BCR engagement in ZAP-70-transfected cells was CCR7 up-regulation, this being impaired by ERK1/2 inhibition and translating into both increased signaling and migration toward CCL21. Primary CLL subclones with high ZAP-70 expression showed increased migration toward CCL21. In conclusion, ZAP-70 ectopic expression led to enhanced BCR signaling after IgM stimulation and increased the expression of CCR7 predominantly via ERK1/2, increasing the response and migration toward CCL21. In primary CLL samples, cellular subsets with high ZAP-70 expression had increased expression of adhesion molecules and chemokine receptors in addition to an enhanced ability to migrate toward CCL21.
Asunto(s)
Linfocitos B/citología , Linfoma de Burkitt/inmunología , Quimiocina CCL21/inmunología , Quimiotaxis , Leucemia Linfocítica Crónica de Células B/inmunología , Receptores CCR7/inmunología , Proteína Tirosina Quinasa ZAP-70/inmunología , Linfocitos B/inmunología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoglobulina M/inmunología , Sistema de Señalización de MAP Quinasas , Receptores CCR7/genética , Células Tumorales CultivadasRESUMEN
The proliferation of new techniques that allow a multiparametric study of gene expression, the mutational state of genomic DNA, DNA methylation and the phosphorylation of receptor and adaptor proteins has led to an increased understanding of the origin of different cancers, the definition of new prognosis markers and the response to treatment profiles. Gene profiling studies on chronic lymphocytic leukaemia (CLL) are at the origin of new prognosis markers such as zeta-associated protein-70 (ZAP-70), LPL and CLLU1, which, at present, are under study for their application to clinical practice. An increased resolution in the mutational state at genomic level has underscored the importance of deletion 13q14 at the origin of CLL and 13q and 17p in response to treatment. Some new insights regarding changes in gene expression in CLL cells depending on the microenvironment have been described, but more work is yet to be done in the field.
Asunto(s)
Perfilación de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , ADP-Ribosil Ciclasa 1/genética , Biomarcadores de Tumor/análisis , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/terapia , Lipoproteína Lipasa/genética , Glicoproteínas de Membrana/genética , MicroARNs/genética , Proteínas de Neoplasias/genética , Pronóstico , ARN Largo no Codificante , Proteína Tirosina Quinasa ZAP-70/genéticaRESUMEN
The behavior of classic Hodgkin lymphoma (cHL) is determined by both the intrinsic features of the tumor cells and the characteristics of the microenvironment, making the analysis of entire lymph nodes an effective approach to understanding the disease. We examined the influence of our previously reported 25-microRNA signature for cHL on clinical outcome in 89 homogeneously treated cHL patients with a median follow-up of 80 months. Patients with low miR-135a expression had a higher probability of relapse (P = .04) and a shorter disease-free survival (P = .02). Functional analysis of cHL cell lines showed that mature miR-135a levels increased after pre-miR-135a transfection, causing apoptosis and decreased cell growth. Target analysis showed a direct regulation by miR-135a of JAK2, a cytoplasmic tyrosine kinase involved in a specific subset of cytokine receptor signaling pathways. miR-135a-mediated JAK2 down-regulation led to decreased mRNA and protein levels of the antiapoptotic gene Bcl-xL, suggesting a role for Bcl-xL in miR-135a/JAK2-mediated apoptosis. Our findings confirm the critical role of miR-135a in the survival of cHL cells and in the prognosis of cHL patients, indicating that novel treatment approaches targeting miR-135a may potentially benefit these patients.