Publication details

MicroRNA miR-34a downregulates FOXP1 during DNA damage response to limit BCR signalling in chronic lymphocytic leukaemia B cells

Title in English MicroRNA miR-34a downregulates FOXP1 during DNA damage response to limit BCR signalling in chronic lymphocytic leukaemia B cells.
Authors

AMRUZ ČERNÁ Kateřina OPPELT Jan CHOCHOLA Václav MUSILOVÁ Kateřina ŠEDA Václav PAVLASOVÁ Gabriela RADOVÁ Lenka ARIGONI M. CALOGERO R.A. BENES V. TRBUŠEK Martin BRYCHTOVÁ Yvona DOUBEK Michael MAYER Jiří POSPÍŠILOVÁ Šárka MRÁZ Marek

Year of publication 2019
Type Article in Periodical
Magazine / Source Leukemia
MU Faculty or unit

Central European Institute of Technology

Citation
Web https://www.nature.com/articles/s41375-018-0230-x
Doi http://dx.doi.org/10.1038/s41375-018-0230-x
Keywords TRANSCRIPTION FACTOR; TP53 MUTATION; EXPRESSION; RECEPTOR; LYMPHOMA; SURVIVAL; TRANSFORMATION; FLUDARABINE; PROGRESSION; REPRESSION
Description The variable clinical course in chronic lymphocytic leukaemia (CLL) largely depends on p53 functionality and B-cell receptor (BCR) signalling propensity; however, it is unclear if there is any crosstalk between these pathways. We show that DNA damage response (DDR) activation leads to down-modulating the transcriptional factor FOXP1, which functions as a positive BCR signalling regulator and its high levels are associated with worse CLL prognosis. We identified microRNA (miRNA) miR-34a as the most prominently upregulated miRNA during DDR in CLL cells in vitro and in vivo during FCR therapy (fludarabine, cyclophosphamide, rituximab). MiR-34a induced by DDR activation and p53 stabilization potently represses FOXP1 expression by binding in its 3'-UTR. The low FOXP1 levels limit BCR signalling partially via derepressing BCR-inhibitory molecule CD22. We also show that low miR-34a levels can be used as a biomarker for worse response or shorter progression free survival in CLL patients treated with FCR chemoimmunotherapy, and shorter overall survival, irrespective of TP53 status. Additionally, we have developed a method for the absolute quantification of miR-34a copies and defined precise prognostic/predictive cutoffs. Overall, herein, we reveal for the first time that B cells limit their BCR signalling during DDR by down-modulating FOXP1 via DDR-p53/miR-34a axis.
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