miR-150 downregulation contributes to the high-grade transformation of follicular lymphoma by upregulating FOXP1 levels

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Authors	MUSILOVÁ Kateřina DEVÁN Ján AMRUZ ČERNÁ Kateřina ŠEDA Václav PAVLASOVÁ Gabriela SHARMA Sonali OPPELT Jan PYTLIK R. PROCHAZKA V. PROUZOVA Z. TRBUŠEK Martin ZLAMALIKOVA L. LISKOVA K. KRUZOVA L. JAROSOVA M. MAREČKOVÁ Andrea KORNAUTH C. SIMONITSCH-KLUPP I. SCHIEFER A.I. MERKEL O. MOCIKOVA H. BURDA P. POLAKOVA K.M. KREN L. MAYER Jiří ZENT C.S. TRNENY M. EVANS A.G. JANÍKOVÁ Andrea MRÁZ Marek
Year of publication	2018
Type	Article in Periodical
Magazine / Source	Blood
MU Faculty or unit	Central European Institute of Technology
Citation
Web	http://www.bloodjournal.org/content/132/22/2389?sso-checked=true
Doi	http://dx.doi.org/10.1182/blood-2018-06-855502
Keywords	B-CELL LYMPHOMA; TRANSCRIPTION FACTOR; T-CELLS; C-MYC; HISTOLOGIC TRANSFORMATION; COPY-NUMBER; KAPPA-B; EXPRESSION; SURVIVAL; MICRORNAS
Description	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 ofMYC 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 (similar to 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-kappa B 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 theMYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.
Related projects:	CEITEC 2020 Vliv terapeutické inhibice BCR signalizace na genovou expresi u B buněčných malignit a její prognostický a prediktivní význam ÚLOHA MICRORNA A JEJICH CÍLOVÝCH MOLEKUL V TRANSFORMACI FOLIKULÁRNÍHO LYMFOMU A AGRESIVITĚ CHRONICKÉ LYMFOCYTÁRNÍ LEUKÉMIE