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.

1st Department of Medicine Department of Hematology General University Hospital Prague and 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Clinical Pathology Medical University Vienna Vienna Austria

Department of Hemato Oncology Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc Czech Republic

Department of Internal Medicine and Hematology University Hospital Kralovske Vinohrady and 3rd Faculty of Medicine Charles University Prague Czech Republic

Department of Internal Medicine Hematology and Oncology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pathology University Hospital Brno Brno Czech Republic

Departments of Pathology and Laboratory Medicine and Medicine University of Rochester Medical Center School of Medicine and Dentistry Rochester NY

Institute of Hematology and Blood Transfusion Prague Czech Republic

Institute of Pathological Physiology 1st Medical Faculty Charles University Prague Czech Republic; and

Molecular Medicine Central European Institute of Technology Masaryk University Brno Czech Republic

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