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Chronic lymphocytic leukemia

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

Abstract

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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Acknowledgements

This work was supported by the Czech Science Foundation (project No. 16-13334Y), the MUNI/A/0968/2017 with the support of the Specific University Research Grant, as provided by the Ministry of Education, Youth and Sports of the Czech Republic and financially supported by the Ministry of Education, Youth and Sports of the Czech Republic under the project CEITEC 2020 (LQ1601). This project has also received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 692298. This article reflects only the author’s view and the Research Executive Agency is not responsible for any use that may be made of the information it contains.

Author contributions

K.C. performed experiments, analysed data and wrote the paper; V.C., K.M. and G.P. performed experiments; V.S. interpreted the data; J.O. and L.R. analysed the data; M.A. and R.A.C. performed Illumina NGS sequencing; other co-authors provided patients’ samples, clinical data and interpreted data, M.M. designed the study, interpreted data and wrote the paper. All authors edited and approved the paper for submission.

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Correspondence to Marek Mraz.

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Cerna, K., Oppelt, J., Chochola, V. et al. MicroRNA miR-34a downregulates FOXP1 during DNA damage response to limit BCR signalling in chronic lymphocytic leukaemia B cells. Leukemia 33, 403–414 (2019). https://doi.org/10.1038/s41375-018-0230-x

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