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

K. Cerna, J. Oppelt, V. Chochola, K. Musilova, V. Seda, G. Pavlasova, L. Radova, M. Arigoni, RA. Calogero, V. Benes, M. Trbusek, Y. Brychtova, M. Doubek, J. Mayer, S. Pospisilova, M. Mraz,

. 2019 ; 33 (2) : 403-414. [pub] 20180815

Language English Country England, Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc19028266

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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$a Cerna, Katerina $u Molecular Medicine, CEITEC MU, Brno, Czech Republic. Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine MU, Brno, Czech Republic.
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$a 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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$a Oppelt, Jan $u Molecular Medicine, CEITEC MU, Brno, Czech Republic. National Centre for Biomolecular Research, Faculty of Science, MU, Brno, Czech Republic.
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$a Chochola, Vaclav $u Molecular Medicine, CEITEC MU, Brno, Czech Republic.
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$a Musilová, Kateřina $7 xx0244506 $u Molecular Medicine, CEITEC MU, Brno, Czech Republic. Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine MU, Brno, Czech Republic.
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$a Seda, Vaclav $u Molecular Medicine, CEITEC MU, Brno, Czech Republic. Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine MU, Brno, Czech Republic.
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$a Pavlasova, Gabriela $u Molecular Medicine, CEITEC MU, Brno, Czech Republic. Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine MU, Brno, Czech Republic.
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$a Radova, Lenka $u Molecular Medicine, CEITEC MU, Brno, Czech Republic.
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$a Arigoni, Maddalena $u Bioinformatics and Genomics Unit, MBC Centro di Biotecnologie Molecolari, Torino, Italy.
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$a Calogero, Raffaele A $u Bioinformatics and Genomics Unit, MBC Centro di Biotecnologie Molecolari, Torino, Italy.
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$a Benes, Vladimir $u Genomics Core Facility, EMBL Heidelberg, Heidelberg, Germany.
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$a Trbusek, Martin $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine MU, Brno, Czech Republic.
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$a Brychtova, Yvona $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine MU, Brno, Czech Republic.
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$a Doubek, Michael $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine MU, Brno, Czech Republic.
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$a Mayer, Jiri $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine MU, Brno, Czech Republic.
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$a Pospisilova, Sarka $u Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine MU, Brno, Czech Republic.
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$a Mraz, Marek $u Molecular Medicine, CEITEC MU, Brno, Czech Republic. marek.mraz@email.cz. Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine MU, Brno, Czech Republic. marek.mraz@email.cz.
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