RESUMEN
Myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), and remarkably shortens survival. Although JAK2V617F and CALR allele burden are the main transformation risk factors, inflammation plays a critical role by driving clonal expansion toward end-stage disease. NF-κB is a key mediator of inflammation-induced carcinogenesis. Here, we explored the involvement of miR-146a, a brake in NF-κB signaling, in MPN susceptibility and progression. rs2910164 and rs2431697, that affect miR-146a expression, were analyzed in 967 MPN (320 PV/333 ET/314 MF) patients and 600 controls. We found that rs2431697 TT genotype was associated with MF, particularly with post-PV/ET MF (HR = 1.5; p < 0.05). Among 232 PV/ET patients (follow-up time=8.5 years), 18 (7.8%) progressed to MF, being MF-free-survival shorter for rs2431697 TT than CC + CT patients (p = 0.01). Multivariate analysis identified TT genotype as independent predictor of MF progression. In addition, TT (vs. CC + CT) patients showed increased plasma inflammatory cytokines. Finally, miR-146a-/- mice showed significantly higher Stat3 activity with aging, parallel to the development of the MF-like phenotype. In conclusion, we demonstrated that rs2431697 TT genotype is an early predictor of MF progression independent of the JAK2V617F allele burden. Low levels of miR-146a contribute to the MF phenotype by increasing Stat3 signaling.
Asunto(s)
MicroARNs/genética , Trastornos Mieloproliferativos/genética , Mielofibrosis Primaria/genética , Anciano , Alelos , Animales , Citocinas/genética , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Inflamación/genética , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Mutación/genética , Trastornos Mieloproliferativos/patología , FN-kappa B/genética , Policitemia Vera/genética , Policitemia Vera/patología , Transducción de Señal/genética , Trombocitemia Esencial/genética , Trombocitemia Esencial/patologíaRESUMEN
An increasing numbers of patients are being diagnosed with asymptomatic early-stage chronic lymphocytic leukemia (CLL), with no treatment indication at baseline. We applied a high-throughput deep-targeted analysis, especially designed for covering widely TP53 and ATM genes, in 180 patients with inactive disease at diagnosis, to test the independent prognostic value of CLL somatic recurrent mutations. We found that 40/180 patients harbored at least one acquired variant with ATM (n=17, 9.4%), NOTCH1 (n=14, 7.7%), TP53 (n=14, 7.7%) and SF3B1 (n=10, 5.5%) as most prevalent mutated genes. Harboring one 'sub-Sanger' TP53 mutation granted an independent 3.5-fold increase of probability of needing treatment. Those patients with a double-hit ATM lesion (mutation+11q deletion) had the shorter median time to first treatment (17 months). We found that a genomic variable: TP53 mutations, most of them under the sensitivity of conventional techniques; a cell phenotypic factor: CD38-positive expression; and a classical marker as ß2-microglobulin, remained as the unique independent predictors of outcome. The high-throughput determination of TP53 status, particularly in this set of patients frequently lacking high-risk chromosomal aberrations, emerges as a key step, not only for prediction modeling, but also for exploring mutation-specific therapeutic approaches and minimal residual disease monitoring.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/genética , Mutación , Anciano , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Genes Relacionados con las Neoplasias , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
Epidemiologic studies have revealed that modification of the levels of individual components of the hemostatic system may have effects on the development of thrombosis or hemorrhage. To maintain the necessary equilibrium, the hemostatic system is finely regulated. It is known that acquired factors and/or alterations in genes (single-nucleotide polymorphisms or mutations) may be the cause of interindividual differences or exacerbated levels of hemostatic proteins in plasma, but there are still many non-characterized factors that provoke such variations. The search for new elements, such as microRNAs (miRNAs), a family of small non-coding RNAs that are novel regulators of protein expression, may reveal an additional layer at which to investigate the causes of hemostatic diseases. In this review, we discuss the latest developments in research into the role of miRNAs in the regulation of several hemostatic factors, and the potential use of miRNAs as prognostic or diagnostic tools in hemostasis and thrombosis.
