The surprising role of microRNAs in the DNA damage and B cell receptor signalling in malignant B cells

Kód výsledku v IS VaVaI

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Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

The surprising role of microRNAs in the DNA damage and B cell receptor signalling in malignant B cells

Popis výsledku v původním jazyce

Presenting author B Cell Receptor (BCR) signalling is fundamental for the maturation, survival, and proliferation of B cells, and B cell malignancies frequently harbor mutations in this pathway and/or complex deregulation of interconnected signalling. This is underscored by the remarkable clinical effect of inhibitors targeting BCR-associated kinases, especially in chronic lymphocytic leukemia (CLL); however, in CLL the BCR pathway deregulation is not driven by a mutational mechanism. The differences in BCR signalling propensity contribute to variable prognosis in CLL and other &quot;mature&quot; B cell malignancies. Interestingly, it is plausible that a normal (or malignant) B cell has to concurrently resolve a situation where its DNA is damaged, leading to p53 stabilization, while a strong pro-proliferative/pro-survival signal is &quot;coming&quot; from its BCR at the same time, due to antigen binding. This should be precisely regulated since a B cell possesses the physiological potential for clonal proliferation, and any unrepaired genetic aberration would greatly increase the risk of a malignancy. Indeed, we have observed that when CLL B cells experience DNA damage, their responsiveness to BCR signalling becomes limited, and a similar phenotype can be observed upon forced p53 stabilization by a small molecule Nutlin-3a. We have further described that p53 accumulation induces the microRNA miR-34a, which acts as a very potent repressor of a transcription factor FOXP1. FOXP1 is a known positive BCR signalling regulator. We have shown that in mature B cells, FOXP1 acts as a transcriptional repressor of a cell-membrane molecule CD22, which contains immunoreceptor tyrosine inhibitory motifs and serves as a docking site for phosphatases. The down-modulation of FOXP1 during DNA damage response (DDR) leads to CD22 upregulation, and we suggest that this allows phosphatases such as SHIP1/SHP1 to dock more efficiently to the cell membrane and BCR-signalosome, and thus limit BCR signalling relatively &quot;upstream&quot;. We have also shown that clinically used DNA damaging drugs such as fludarabine (or doxorubicin) partially function by inhibiting BCR signalling. The p53 aberrations affect this regulatory mechanism, and the low miR-34a levels can serve as an independent predictor of the patient response to chemo-immunotherapy in CLL. The miR-34a levels are low in B cells without DDR induction, and thus this miRNA probably only contributes to FOXP1/CD22 regulation when wild-type p53 is accumulated in the cell. Altogether, this shows for the first time that DDR leads to repression of signalling from the surface BCR via a miR-34a- -mediated FOXP1 down-modulation.

Název v anglickém jazyce

The surprising role of microRNAs in the DNA damage and B cell receptor signalling in malignant B cells

Popis výsledku anglicky

Presenting author B Cell Receptor (BCR) signalling is fundamental for the maturation, survival, and proliferation of B cells, and B cell malignancies frequently harbor mutations in this pathway and/or complex deregulation of interconnected signalling. This is underscored by the remarkable clinical effect of inhibitors targeting BCR-associated kinases, especially in chronic lymphocytic leukemia (CLL); however, in CLL the BCR pathway deregulation is not driven by a mutational mechanism. The differences in BCR signalling propensity contribute to variable prognosis in CLL and other &quot;mature&quot; B cell malignancies. Interestingly, it is plausible that a normal (or malignant) B cell has to concurrently resolve a situation where its DNA is damaged, leading to p53 stabilization, while a strong pro-proliferative/pro-survival signal is &quot;coming&quot; from its BCR at the same time, due to antigen binding. This should be precisely regulated since a B cell possesses the physiological potential for clonal proliferation, and any unrepaired genetic aberration would greatly increase the risk of a malignancy. Indeed, we have observed that when CLL B cells experience DNA damage, their responsiveness to BCR signalling becomes limited, and a similar phenotype can be observed upon forced p53 stabilization by a small molecule Nutlin-3a. We have further described that p53 accumulation induces the microRNA miR-34a, which acts as a very potent repressor of a transcription factor FOXP1. FOXP1 is a known positive BCR signalling regulator. We have shown that in mature B cells, FOXP1 acts as a transcriptional repressor of a cell-membrane molecule CD22, which contains immunoreceptor tyrosine inhibitory motifs and serves as a docking site for phosphatases. The down-modulation of FOXP1 during DNA damage response (DDR) leads to CD22 upregulation, and we suggest that this allows phosphatases such as SHIP1/SHP1 to dock more efficiently to the cell membrane and BCR-signalosome, and thus limit BCR signalling relatively &quot;upstream&quot;. We have also shown that clinically used DNA damaging drugs such as fludarabine (or doxorubicin) partially function by inhibiting BCR signalling. The p53 aberrations affect this regulatory mechanism, and the low miR-34a levels can serve as an independent predictor of the patient response to chemo-immunotherapy in CLL. The miR-34a levels are low in B cells without DDR induction, and thus this miRNA probably only contributes to FOXP1/CD22 regulation when wild-type p53 is accumulated in the cell. Altogether, this shows for the first time that DDR leads to repression of signalling from the surface BCR via a miR-34a- -mediated FOXP1 down-modulation.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30204 - Oncology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů