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

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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

Druh Článek v odborném periodiku
Časopis / Zdroj Leukemia
Fakulta / Pracoviště MU

Středoevropský technologický institut

Citace
www https://www.nature.com/articles/s41375-018-0230-x
Doi http://dx.doi.org/10.1038/s41375-018-0230-x
Klíčová slova TRANSCRIPTION FACTOR; TP53 MUTATION; EXPRESSION; RECEPTOR; LYMPHOMA; SURVIVAL; TRANSFORMATION; FLUDARABINE; PROGRESSION; REPRESSION
Popis 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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