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 ArribaRESUMEN
B-cell neoplasms represent a clinically heterogeneous group of hematologic malignancies with considerably diverse genomic architecture recently endorsed by next-generation sequencing (NGS) studies. Because multiple genetic defects have a potential or confirmed clinical impact, a tendency toward more comprehensive testing of diagnostic, prognostic, and predictive markers is desired. This study introduces the design, validation, and implementation of an integrative, custom-designed, capture-based NGS panel titled LYmphoid NeXt-generation sequencing (LYNX) for the analysis of standard and novel molecular markers in the most common lymphoid neoplasms (chronic lymphocytic leukemia, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma). A single LYNX test provides the following: i) accurate detection of mutations in all coding exons and splice sites of 70 lymphoma-related genes with a sensitivity of 5% variant allele frequency, ii) reliable identification of large genome-wide (≥6 Mb) and recurrent chromosomal aberrations (≥300 kb) in at least 20% of the clonal cell fraction, iii) the assessment of immunoglobulin and T-cell receptor gene rearrangements, and iv) lymphoma-specific translocation detection. Dedicated bioinformatic pipelines were designed to detect all markers mentioned above. The LYNX panel represents a comprehensive, up-to-date tool suitable for routine testing of lymphoid neoplasms with research and clinical applicability. It allows a wide adoption of capture-based targeted NGS in clinical practice and personalized management of patients with lymphoproliferative diseases.
Asunto(s)
Biomarcadores de Tumor , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Leucemia Linfoide/diagnóstico , Leucemia Linfoide/genética , Linfoma/diagnóstico , Linfoma/genética , Aberraciones Cromosómicas , Biología Computacional/métodos , Variaciones en el Número de Copia de ADN , Variación Genética , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Mutación INDEL , Técnicas de Diagnóstico Molecular , Pronóstico , Translocación GenéticaRESUMEN
Chronic benign CD8+ proliferation is a rare syndrome that can take the form of a variety of other diseases. Peripheral adenopathy, cytopenia, and infiltration of the liver, kidneys, bowels, or other organs are the most common clinical presentations of the syndrome. CD8+ expansion can be clonal and nonclonal. It generally occurs in patients with innate or acquired immunodeficiency (HIV+) or in patients receiving immunosuppressive therapy. It has been found repeatedly in patients who developed severe hypogammaglobulinemia after treatment with rituximab. Diagnosis of the disease can be difficult because it can mimic relapse of a lymphoma, and a common biopsy examination cannot identify the problem at first. The authors describe a case of a patient pretreated with rituximab who developed agammaglobulinemia and peripheral adenopathy. Biopsy of an enlarged lymph node showed "reactive lymphadenitis." Additionally, a flow-cytometric examination revealed a pathological population of CD8+ lymphocytes. The treatment, which differed from treatments of lymphoma relapse, consisted of corticosteroids and IVIG substitutions and has led to a regression of clinical symptoms. With more frequent usage of rituximab, one can expect increased occurrence of a very rare CD8+ expansion that can reliably emulate the relapse of a lymphoma.
RESUMEN
Mantle cell lymphoma (MCL) is characterized by the hallmark t(11;14)(q13;q32) translocation, leading to cyclin D1 over-expression. Additionally, disrupting the DNA damage response pathway through ATM or TP53 defects plays an important role in MCL pathogenesis. Using deep next-generation sequencing we analyzed the mutual composition of ATM and TP53 mutations in 72 MCL patients, and assessed their impact on progression-free survival (PFS) and overall survival (OS). Mutated ATM and TP53 alleles were found in 51% (37/72) and 22% (16/72) of the cases examined, respectively, with only three patients harboring mutations in both genes. Only a mutated TP53 gene was associated with the significantly reduced PFS and OS and the same output was observed when ATM and TP53 defective groups included also sole deletions 11q and 17p, respectively. Determining the exact ATM/p53 pathway dysfunction may influence the selection of MCL patients for innovative therapies based on the targeted inhibition of selected proteins.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Predisposición Genética a la Enfermedad , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/patología , Mutación , Proteína p53 Supresora de Tumor/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Biomarcadores de Tumor , Femenino , Estudios de Asociación Genética , Humanos , Linfoma de Células del Manto/mortalidad , Linfoma de Células del Manto/terapia , Masculino , Pronóstico , Factores de Transcripción SOXC/genética , Factores de Transcripción SOXC/metabolismo , Eliminación de Secuencia , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Follicular lymphoma (FL) is highly associated with the molecular rearrangement BCL2/IGH. Although BCL2/IGH has been studied many times in follicular lymphoma, its real clinical value remains controversial. In this study, we performed quantitative testing by real-time polymerase chain reaction in 56 FL patients with median follow-up of 44 months (range, 9-102 months); chemotherapy was administered in 52 of 56 cases. Pretreatment numbers of BCL2/IGH varied in wide ranges, with a median of 2947 (range, 0-1,261,013) copies/10(6) cellular equivalent in peripheral blood (PB) and 4650 copies/10(6) cellular equivalent (range, 1-1,056,813) in bone marrow (BM), the difference between PB and BM was significant (p = 0.006). Pretreatment of BCL2/IGH quantities were correlated to clinical parameters (e.g., age, stage, sex, lactate dehydrogenase, B symptoms, grade, bulky disease, chemotherapy regimen) and to progression free-survival. Advanced clinical stage (III and IV) and microscopic BM involvement were significantly associated with higher numbers of BCL2/IGH in PB (p < 0.05) and in BM (p = 0.05), regardless all or newly diagnosed patients were evaluated. High pretreatment burden of BCL2/IGH was associated with significantly shorter progression-free survival; p = 0.003 and p = 0.047 for PB and BM, respectively. In conclusion, pretreatment quantity of BCL2/IGH in PB or BM seems to mirror the extent of disease and can provide an auxiliary prognostic parameter in FL. Our results also support evidence of the negative prognostic value of microscopic BM involvement in FL.