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

J 2019

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

AMRUZ ČERNÁ, Kateřina, Jan OPPELT, Václav CHOCHOLA, Kateřina MUSILOVÁ, Václav ŠEDA et. al.

Basic information

Original name

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

Authors

AMRUZ ČERNÁ, Kateřina (203 Czech Republic, belonging to the institution), Jan OPPELT (203 Czech Republic, belonging to the institution), Václav CHOCHOLA (203 Czech Republic, belonging to the institution), Kateřina MUSILOVÁ (203 Czech Republic, belonging to the institution), Václav ŠEDA (203 Czech Republic, belonging to the institution), Gabriela PAVLASOVÁ (203 Czech Republic, belonging to the institution), Lenka RADOVÁ (203 Czech Republic, belonging to the institution), M. ARIGONI (380 Italy), R.A. CALOGERO (380 Italy), V. BENES (276 Germany), Martin TRBUŠEK (203 Czech Republic, belonging to the institution), Yvona BRYCHTOVÁ (203 Czech Republic, belonging to the institution), Michael DOUBEK (203 Czech Republic, belonging to the institution), Jiří MAYER (203 Czech Republic, belonging to the institution), Šárka POSPÍŠILOVÁ (203 Czech Republic, belonging to the institution) and Marek MRÁZ (203 Czech Republic, guarantor, belonging to the institution)

Edition

Leukemia, London, Nature Publishing Group, 2019, 0887-6924

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30205 Hematology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 8.665

RIV identification code

RIV/00216224:14740/19:00109077

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1038/s41375-018-0230-x

UT WoS

000457857300013

Keywords in English

TRANSCRIPTION FACTOR; TP53 MUTATION; EXPRESSION; RECEPTOR; LYMPHOMA; SURVIVAL; TRANSFORMATION; FLUDARABINE; PROGRESSION; REPRESSION

Abstract

V originále

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.

Links

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR

MUNI/A/0968/2017, interní kód MU

Name: Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit V (Acronym: VýDiTeHeMA V)

Investor: Masaryk University, Category A

692298, interní kód MU

Name: MEDGENET - Medical genomics and epigenomics network (Acronym: MEDGENET)

Investor: European Union, Spreading excellence and widening participation

90091, large research infrastructures

Name: NCMG

Citovat

AMRUZ ČERNÁ, Kateřina, Jan OPPELT, Václav CHOCHOLA, Kateřina MUSILOVÁ, Václav ŠEDA, Gabriela PAVLASOVÁ, Lenka RADOVÁ, M. ARIGONI, R.A. CALOGERO, V. BENES, Martin TRBUŠEK, Yvona BRYCHTOVÁ, Michael DOUBEK, Jiří MAYER, Šárka POSPÍŠILOVÁ and Marek MRÁZ. MicroRNA miR-34a downregulates FOXP1 during DNA damage response to limit BCR signalling in chronic lymphocytic leukaemia B cells (MicroRNA miR-34a downregulates FOXP1 during DNA damage response to limit BCR signalling in chronic lymphocytic leukaemia B cells.). Leukemia. London: Nature Publishing Group, 2019, vol. 33, No 2, p. 403-414. ISSN 0887-6924. Available from: https://dx.doi.org/10.1038/s41375-018-0230-x.

@article{1492287,
   author = {Amruz Černá, Kateřina and Oppelt, Jan and Chochola, Václav and Musilová, Kateřina and Šeda, Václav and Pavlasová, Gabriela and Radová, Lenka and Arigoni, M. and Calogero, R.A. and Benes, V. and Trbušek, Martin and Brychtová, Yvona and Doubek, Michael and Mayer, Jiří and Pospíšilová, Šárka and Mráz, Marek},
   article_location = {London},
   article_number = {2},
   doi = {http://dx.doi.org/10.1038/s41375-018-0230-x},
   keywords = {TRANSCRIPTION FACTOR; TP53 MUTATION; EXPRESSION; RECEPTOR; LYMPHOMA; SURVIVAL; TRANSFORMATION; FLUDARABINE; PROGRESSION; REPRESSION},
   language = {eng},
   issn = {0887-6924},
   journal = {Leukemia},
   title = {MicroRNA miR-34a downregulates FOXP1 during DNA damage response to limit BCR signalling in chronic lymphocytic leukaemia B cells},
   url = {https://www.nature.com/articles/s41375-018-0230-x},
   volume = {33},
   year = {2019}
}

TY  - JOUR
ID  - 1492287
AU  - Amruz Černá, Kateřina - Oppelt, Jan - Chochola, Václav - Musilová, Kateřina - Šeda, Václav - Pavlasová, Gabriela - Radová, Lenka - Arigoni, M. - Calogero, R.A. - Benes, V. - Trbušek, Martin - Brychtová, Yvona - Doubek, Michael - Mayer, Jiří - Pospíšilová, Šárka - Mráz, Marek
PY  - 2019
TI  - MicroRNA miR-34a downregulates FOXP1 during DNA damage response to limit BCR signalling in chronic lymphocytic leukaemia B cells
JF  - Leukemia
VL  - 33
IS  - 2
SP  - 403-414
EP  - 403-414
PB  - Nature Publishing Group
SN  - 08876924
KW  - TRANSCRIPTION FACTOR
KW  - TP53 MUTATION
KW  - EXPRESSION
KW  - RECEPTOR
KW  - LYMPHOMA
KW  - SURVIVAL
KW  - TRANSFORMATION
KW  - FLUDARABINE
KW  - PROGRESSION
KW  - REPRESSION
UR  - https://www.nature.com/articles/s41375-018-0230-x
L2  - https://www.nature.com/articles/s41375-018-0230-x
N2  - 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.
ER  -

AMRUZ ČERNÁ, Kateřina, Jan OPPELT, Václav CHOCHOLA, Kateřina MUSILOVÁ, Václav ŠEDA, Gabriela PAVLASOVÁ, Lenka RADOVÁ, M. ARIGONI, R.A. CALOGERO, V. BENES, Martin TRBUŠEK, Yvona BRYCHTOVÁ, Michael DOUBEK, Jiří MAYER, Šárka POSPÍŠILOVÁ and Marek MRÁZ. MicroRNA miR-34a downregulates FOXP1 during DNA damage response to limit BCR signalling in chronic lymphocytic leukaemia B cells (MicroRNA miR-34a downregulates FOXP1 during DNA damage response to limit BCR signalling in chronic lymphocytic leukaemia B cells.). \textit{Leukemia}. London: Nature Publishing Group, 2019, vol.~33, No~2, p.~403-414. ISSN~0887-6924. Available from: https://dx.doi.org/10.1038/s41375-018-0230-x.

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