MicroRNA miR-34a downregulates FOXP1 during DNA damage response to limit BCR signalling in chronic lymphocytic leukaemia B cells.
Leukemia
; 33(2): 403-414, 2019 02.
Article
em En
| MEDLINE
| ID: mdl-30111844
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.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
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Dano ao DNA
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Receptores de Antígenos de Linfócitos B
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Leucemia Linfocítica Crônica de Células B
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Protocolos de Quimioterapia Combinada Antineoplásica
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Biomarcadores Tumorais
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MicroRNAs
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Fatores de Transcrição Forkhead
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article