RESUMEN
Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly downmodulated in all examined tFLs (â¼3.5-fold), and observed that high levels of MYC are responsible for repressing miR-150 in tFL by binding in its upstream region. This MYC-mediated repression of miR-150 in B cells is not dependent on LIN28A/B proteins, which influence the maturation of miR-150 precursor (pri-miR-150) in myeloid cells. We also demonstrated that low miR-150 levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of miR-150 and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that miR-150 could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.
Asunto(s)
Factores de Transcripción Forkhead/genética , Regulación Neoplásica de la Expresión Génica , Linfoma Folicular/genética , MicroARNs/genética , Proteínas Represoras/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Regulación hacia Abajo , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Pronóstico , Proteínas Proto-Oncogénicas c-myc/genética , Activación Transcripcional , Regulación hacia ArribaAsunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 6/genética , Proteína Forkhead Box O3 , Regulación Leucémica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B , Proteínas de Neoplasias , Adulto , Anciano , Anciano de 80 o más Años , República Checa , Supervivencia sin Enfermedad , Femenino , Proteína Forkhead Box O3/biosíntesis , Proteína Forkhead Box O3/genética , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Tasa de SupervivenciaRESUMEN
BACKGROUND: Better risk-stratification of patients with chronic lymphocytic leukemia (CLL) and identification of subsets of ultra-high-risk (HR)-CLL patients are crucial in the contemporary era of an expanded therapeutic armamentarium for CLL. METHODS: A multivariate patient similarity network and clustering was applied to assess the prognostic values of routine genetic, laboratory, and clinical factors and to identify subsets of ultra-HR-CLL patients. The study cohort consisted of 116 HR-CLL patients (F/M 36/80, median age 63 yrs) carrying del(11q), del(17p)/TP53 mutations and/or complex karyotype (CK) at the time of diagnosis. RESULTS: Three major subsets based on the presence of key prognostic variables as genetic aberrations, bulky lymphadenopathy, splenomegaly, and gender: profile (P)-I (n = 34, men/women with CK + no del(17p)/TP53 mutations), P-II (n = 47, predominantly men with del(11q) + no CK + no del(17p)/TP53 mutations), and P-III (n = 35, men/women with del(17p)/TP53 mutations, with/without del(11q) and CK) were revealed. Subanalysis of major subsets identified three ultra-HR-CLL groups: men with TP53 disruption with/without CK, women with TP53 disruption with CK and men/women with CK + del(11q) with poor short-term outcomes (25% deaths/12 mo). Besides confirming the combinations of known risk-factors, the used patient similarity network added further refinement of subsets of HR-CLL patients who may profit from different targeted drugs. CONCLUSIONS: This study showed for the first time in hemato-oncology the usefulness of the multivariate patient similarity networks for stratification of HR-CLL patients. This approach shows the potential for clinical implementation of precision medicine, which is especially important in view of an armamentarium of novel targeted drugs.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/terapia , Adulto , Anciano , Anciano de 80 o más Años , Análisis por Conglomerados , Estudios de Cohortes , Análisis Mutacional de ADN , Árboles de Decisión , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , Análisis Multivariante , Redes Neurales de la Computación , Medicina de Precisión/métodos , Valor Predictivo de las Pruebas , Pronóstico , Medición de RiesgoRESUMEN
OBJECTIVES: A complex karyotype (CK) is considered a poor prognostic marker in chronic lymphocytic leukemia (CLL). METHODS: The study analyzed 644 untreated CLL patients (pts) using conventional/molecular cytogenetics to reveal the presence of a CK and its composition and to assess its predictive value. The mutational status ofTP53 was detected by next generation sequencing. RESULTS: A CK was detected in 79 pts (12.3%). Patients with a CK showed shorter overall survival (OS) compared to those without a CK (77 months vs. 115 months, pâ¯<â¯0.0001). Chromosomes most frequently included in a CK were 13, 11, 17, 8, 2, and 6. The most common aberrations in a CK were translocations, numerical changes and dicentric chromosomes (with no effect on OS). Patients with aberrations ofTP53 and ATM were shown to have adverse prognosis comparable to patients with a CK without these abnormalities. A stronger impact of a CK on OS of female and older CLL patients was observed. CONCLUSIONS: The determining of the presence of a CK is essential in modern clinical CLL practice. According to recent studies, the presence of a CK affects clinical and treatment decision-making.