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

• Published in: Leukemia 2019-02, Vol.33 (2), p.403-414
• Main Authors: Cerna, Katerina, Oppelt, Jan, Chochola, Vaclav, Musilova, Katerina, Seda, Vaclav, Pavlasova, Gabriela, Radova, Lenka, Arigoni, Maddalena, Calogero, Raffaele A., Benes, Vladimir, Trbusek, Martin, Brychtova, Yvona, Doubek, Michael, Mayer, Jiri, Pospisilova, Sarka, Mraz, Marek
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/31; 3' Untranslated regions; 38/109; 38/90; 38/91; 631/67/1990/283/1895; 692/699/67/1990/283/1895; 82/1; Activation; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; B cells; B-cell receptor; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer Research; Care and treatment; CD22 antigen; Cellular signal transduction; Chronic lymphocytic leukemia; Critical Care Medicine; Crosstalk; Cyclophosphamide; Cyclophosphamide - administration & dosage; Deoxyribonucleic acid; Development and progression; DNA; DNA damage; DNA Damage - drug effects; DNA Damage - genetics; DNA repair; Female; Fludarabine; Follow-Up Studies; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp1 protein; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic regulation; Health aspects; Hematology; Humans; Intensive; Internal Medicine; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphocytes B; Male; Medical prognosis; Medicine; Medicine & Public Health; MicroRNA; MicroRNAs; MicroRNAs - genetics; Middle Aged; miRNA; Monoclonal antibodies; Oncology; p53 Protein; Prognosis; Receptors, Antigen, B-Cell - genetics; Receptors, Antigen, B-Cell - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Ribonucleic acid; Rituximab; Rituximab - administration & dosage; RNA; Signal Transduction; Signaling; Survival; Survival Rate; Targeted cancer therapy; Transcription (Genetics); Transcription factors; Tumor proteins; Vidarabine - administration & dosage; Vidarabine - analogs & derivatives
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-018-0230-x

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.