RESUMEN
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation of a clonal population of B cells in peripheral blood, bone marrow, and lymphoid organs. More than 10 years ago, lipoprotein lipase (LPL) mRNA was identified as being strongly expressed in patients experiencing a more aggressive phenotype, while CLL patients with an indolent disease course lack expression of this marker. Since then, several reports confirmed the capability of LPL to predict CLL disease evolution at the moment of diagnosis. In contrast, data on the functional implications of LPL in CLL are scarce. LPL exerts a central role in overall lipid metabolism and transport, but plays additional, non-catalytic roles as well. Which of those is more important in the pathogenesis of CLL remains largely unclear. Here, we review the current knowledge on the prognostic and biological relevance of LPL in CLL.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/mortalidad , Lipoproteína Lipasa/metabolismo , Comunicación Celular , Activación Enzimática , Expresión Génica , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Lipoproteína Lipasa/química , Lipoproteína Lipasa/genética , Pronóstico , Transducción de Señal , Relación Estructura-Actividad , Microambiente Tumoral/genéticaRESUMEN
BACKGROUND: The B-cell receptor (BCR) has a key role in the cross-talk between chronic lymphocytic leukaemia (CLL) cells and the tissue microenvironment, which favours disease progression by promoting proliferation and drug resistance. In vitro studies on downstream signalling and functional effects of CLL BCR ligation often report contradictory results, in part owing to the lack of a standardised stimulation protocol. Our aim was to define a biologically relevant and robust in vitro stimulation method with regard to cellular phenotypic and transcriptional responses. METHODS: We evaluated mRNA (FOS, MYC, LPL) and protein (CD54, CD19, CD62L, CD184) expression of genes modulated by BCR triggering in immunoglobulin heavy-chain variable region genes (IGHV)-mutated and -unmutated CLL cells, after stimulation using soluble or immobilised anti-IgM antibodies from different suppliers. RESULTS: The effect of BCR stimulation on gene and protein expression was comparable in all CLL patients, irrespective of IGHV mutation status. However, immobilised anti-IgM stimulation elicited clear and robust changes in gene and protein expression, whereas the response to soluble anti-IgM was far less obvious. CONCLUSIONS: These data indicate that the method of BCR stimulation is of major importance regarding responsiveness of CLL cells in the context of the tumour microenvironment, whereas genetic differences in the BCR pathway are less critical.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/sangre , Receptores de Antígenos de Linfocitos B/sangre , Microambiente Tumoral , Adulto , Anciano , Anticuerpos Antiidiotipos/inmunología , Anticuerpos Antiidiotipos/farmacología , Antígenos CD/biosíntesis , Antígenos CD/genética , Femenino , Citometría de Flujo , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/patología , Lipoproteína Lipasa/biosíntesis , Lipoproteína Lipasa/genética , Masculino , Persona de Mediana Edad , Proteínas Oncogénicas v-fos/biosíntesis , Proteínas Oncogénicas v-fos/genética , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Proteínas Proto-Oncogénicas c-myc/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/inmunologíaRESUMEN
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and is characterized by a heterogeneous clinical course. This variability in clinical course has spiked the search for prognostic markers able to predict patient evolution at the moment of diagnosis. Markers demonstrated to be of value are the mutation status of the immunoglobulin heavy chain variable region genes (IGHV) and lipoprotein lipase (LPL) expression. High LPL mRNA expression has been associated with short treatment free (TFS) and decreased overall survival (OS) in CLL. The LPL SNPs rs301 (TAsunto(s)
Leucemia Linfocítica Crónica de Células B/enzimología
, Leucemia Linfocítica Crónica de Células B/genética
, Lipoproteína Lipasa/genética
, Polimorfismo de Nucleótido Simple/genética
, Adulto
, Anciano
, Anciano de 80 o más Años
, Biomarcadores de Tumor/genética
, Estudios de Cohortes
, Humanos
, Cadenas Pesadas de Inmunoglobulina/genética
, Región Variable de Inmunoglobulina/genética
, Estimación de Kaplan-Meier
, Lipoproteína Lipasa/metabolismo
, Persona de Mediana Edad
, Mutación/genética
, Pronóstico
, ARN Mensajero/genética
, ARN Mensajero/metabolismo
, Resultado del Tratamiento
RESUMEN
Chronic lymphocytic leukaemia (CLL) is a disease with a highly variable prognosis. The clinical course can however be predicted thanks to prognostic markers. Poor prognosis is associated with expression of a B cell receptor (BCR) from unmutated immunoglobulin variable heavy-chain genes (IGHV) and expression of zeta-associated protein of 70 kDa (ZAP70). The reason why ZAP70 expression is associated with poor prognosis and whether the protein has a direct pathogenic function is at present unknown. By transfer of ZAP70 to CLL cells, we show here that expression of ZAP70 in CLL cells leads to increased expression of the nuclear factor (NF)-κB target genes interleukin-1ß (IL1B), IL6 and IL8 upon BCR triggering. This could be blocked by inhibition of NF-κB signalling through inhibition of IκB kinases (IKK). Transcriptome analysis identified a NF-κB RELA signature imposed by ZAP70 expression in BCR-stimulated CLL cells. We conclude that ZAP70 acts directly as an amplifier of NF-κB signalling in CLL cells which could be an underlying mechanism for its association with poor prognosis and which may represent a therapeutic target.
Asunto(s)
Regulación Leucémica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , FN-kappa B/metabolismo , Proteínas de Neoplasias/fisiología , Proteína Tirosina Quinasa ZAP-70/fisiología , Adulto , Anciano , Señalización del Calcio , Electroporación , Femenino , Humanos , Quinasa I-kappa B/antagonistas & inhibidores , Quinasa I-kappa B/fisiología , Imidazoles/farmacología , Cadenas Pesadas de Inmunoglobulina/genética , Inmunoglobulina M/inmunología , Región Variable de Inmunoglobulina/genética , Interleucina-1beta/biosíntesis , Interleucina-1beta/genética , Interleucina-6/biosíntesis , Interleucina-6/genética , Interleucina-8/biosíntesis , Interleucina-8/genética , Interleucinas/biosíntesis , Interleucinas/genética , Células Jurkat , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Pronóstico , Quinoxalinas/farmacología , ARN Mensajero/genética , Receptores de Antígenos de Linfocitos B/inmunología , Proteínas Recombinantes de Fusión/metabolismo , Factor de Transcripción ReIA/fisiología , Transcriptoma , Células Tumorales Cultivadas , Proteína Tirosina Quinasa ZAP-70/biosíntesis , Proteína Tirosina Quinasa ZAP-70/genéticaRESUMEN
Chronic lymphocytic leukemia (CLL) is a disease with variable clinical outcome. Several prognostic factors such as the immunoglobulin heavy chain variable genes (IGHV) mutation status are linked to the B-cell receptor (BCR) complex, supporting a role for triggering the BCR in vivo in the pathogenesis. The miRNA profile upon stimulation and correlation with IGHV mutation status is however unknown. To evaluate the transcriptional response of peripheral blood CLL cells upon BCR stimulation in vitro, miRNA and mRNA expression was measured using hybridization arrays and qPCR. We found both IGHV mutated and unmutated CLL cells to respond with increased expression of MYC and other genes associated with BCR activation, and a phenotype of cell cycle progression. Genome-wide expression studies showed hsa-miR-132-3p/hsa-miR-212 miRNA cluster induction associated with a set of downregulated genes, enriched for genes modulated by BCR activation and amplified by Myc. We conclude that BCR triggering of CLL cells induces a transcriptional response of genes associated with BCR activation, enhanced cell cycle entry and progression and suggest that part of the transcriptional profiles linked to IGHV mutation status observed in isolated peripheral blood are not cell intrinsic but rather secondary to in vivo BCR stimulation.