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

• DOI: 10.1038/s41375-018-0230-x
• Publication Date: 2018-08-15T11:01:52Z
• Authors: Katerina Cerna; Jan Oppelt; Vaclav Chochola; Katerina Musilova; Vaclav Seda; Gabriela Pavlasova; Lenka Radova; Maddalena Arigoni; Raffaele A. Calogero; Vladimir Benes; Martin Trbusek; Yvona Brychtova; Michael Doubek; Jiri Mayer; Sarka Pospisilova; Marek Mraz
• Keywords: Adult; Aged, 80 and over; Male; 0301 basic medicine; Receptors, Antigen, B-Cell; Forkhead Transcription Factors; Middle Aged; Prognosis; Leukemia, Lymphocytic, Chronic, B-Cell; 3. Good health; Gene Expression Regulation, Neoplastic; Repressor Proteins; MicroRNAs; 03 medical and health sciences; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Humans; Female; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cyclophosphamide; DNA Damage; Female; Follow-Up Studies; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; MicroRNAs; Middle Aged; Prognosis; Receptors, Antigen, B-Cell; Repressor Proteins; Rituximab; Signal Transduction; Survival Rate; Vidarabine; Rituximab; Cyclophosphamide; Aged; DNA Damage; Follow-Up Studies

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.