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 (∼3.5-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.

No abstract

The molecular pathogenesis of follicular lymphoma (FL) was partially revealed by the discovery of BCL2 translocations to the region encoding the immunoglobulin heavy chain, which accompany the vast majority of cases. This aberration leads to the ectopic and constitutive expression of anti-apoptotic BCL2 protein in B-cells. Nevertheless, the aberration alone is not sufficient for FL development, which suggests necessity of further genetic aberrations acquisition for neoplastic transformation to FL. Their discovery has been enabled by recent progress in the field of massive parallel sequencing (next generation sequencing), which revealed high number of genetic aberrations connected with onset and progression of FL. The occurrence of many of these aberrations in the early stages of the disease, and the fact that they are shared by the majority of patients with FL, fundamentally changed our former understanding of the disease onset. Furthermore, in a large fraction of patients, FL undergoes histological transformation to a more aggressive lymphoma, which is also associated with specific genetic alterations. In this review, we summarize the current knowledge of molecular pathways connected with FL biology and discuss their role in the context of normal B-cell development. Understanding of FL biology is essential for the development of new targeted therapies and the stratification of patients, and potentially also for the selection of treatment for specific patients who share the same genetic aberrations.Key words: follicular lymphoma - mutation - aberration - apoptosis - epigenetic regulators - microRNA This research was carried out under the project CEITEC 2020 (LQ1601) with financial support from the Ministry of Education, Youth and Sports of the Czech Republic under the National Sustain ability Programme II. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 28. 1. 2017Accepted: 5. 3. 2017.