Blood. 2018 Sept (epub).
miR-150 downregulation contributes to the high-grade transformation of follicular lymphoma by upregulating FOXP1 levels.
, Devan J, Cerna K, Seda V, Pavlasova G, Sharma S, Oppelt J, Pytlik R, Prochazka V, Prouzova Z, Trbusek M, Zlamalikova L, Liskova K, Kruzova L, Jarosova M, Mareckova A, Kornauth C, Simonitsch-Klupp I, Schiefer AI, Merkel O, Mocikova H, Burda P, Machova Polakova K, Kren L, Mayer J, Zent CS, Trneny M, Evans AG, Janikova A, Mraz M
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 (DLBCL). Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying FL transformation are unclear. Here we performed the first profiling of miRNAs' expression in paired samples of FL and tFL and identified five miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly down-modulated in all examined tFL (~3.5-folds, n=13 pairs), 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 BCR and NF-kB signaling in malignant B cells. We have 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 (FFPE) 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 transformation.