miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia
by Targeting TRAF4: an Axis Affected by BCR inhibitors

J 2021

miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: an Axis Affected by BCR inhibitors

SHARMA, Sonali; Gabriela MLADONICKÁ PAVLASOVÁ; Václav ŠEDA; Kateřina AMRUZ ČERNÁ; Eva VOJÁČKOVÁ et al.

Základní údaje

Originální název

miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: an Axis Affected by BCR inhibitors

Autoři

Vydání

Blood, Washington, DC, American Society of Hematology, 2021, 0006-4971

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 25.669

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14740/21:00120080

Organizační jednotka

Středoevropský technologický institut

Klíčová slova anglicky

MYC; miR-29; TRAF4; BCR signaling; BCR inhibitor

Štítky

14110212, 14110230, CF GEN, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 15. 10. 2024 14:23, Ing. Martina Blahová

Anotace

V originále

B cell receptor (BCR) signaling and T cell interactions play a pivotal role in chronic lymphocytic leukemia (CLL) pathogenesis and disease aggressiveness. CLL cells can utilize microRNAs (miRNAs) and their targets to modulate microenvironmental interactions in the lymph node niches. To identify miRNA expression changes in the CLL microenvironment, we performed complex profiling of short non-coding RNAs in this context by comparing CXCR4/CD5 intraclonal cell subpopulations (CXCR4dimCD5bright vs. CXCR4brightCD5dim cells). This identified dozens of differentially expressed miRNAs including several that have previously been shown to modulate BCR signaling (miR-155, miR-150, and miR-22), but also other candidates for a role in microenvironmental interactions. Notably, all three miR-29 family members (miR-29a, miR-29b, miR-29c) were consistently down-modulated in the immune niches, and lower miR-29(a/b/c) levels associated with an increased relative responsiveness of CLL cells to BCR ligation, and significantly shorter overall survival of CLL patients. We identified Tumor-Necrosis Factor Receptor-Associated Factor 4 (TRAF4) as a novel direct target of miR-29s and revealed that higher TRAF4 levels increase CLL responsiveness to CD40 activation and downstream NFkB signaling. In CLL, BCR-represses miR-29 expression via MYC, allowing for concurrent TRAF4 upregulation and stronger CD40-NFkB signaling. This regulatory loop is disrupted by "BCR inhibitors" (BTK inhibitor ibrutinib or PI3K inhibitor idelalisib). In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling/T-cell interactions in a CLL microenvironment and described a novel miR-29-TRAF4-CD40 signaling axis modulated by the BCR activity.

Návaznosti

LQ1601, projekt VaV

Název: CEITEC 2020 (Akronym: CEITEC2020)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC 2020

MUNI/A/1395/2019, interní kód MU

Název: Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VII (Akronym: VýDiTeHeMa VII)

Investor: Masarykova univerzita, Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VII, DO R. 2020_Kategorie A - Specifický výzkum - Studentské výzkumné projekty

NV18-03-00054, projekt VaV

Název: ÚLOHA MICRORNA A JEJICH CÍLOVÝCH MOLEKUL V TRANSFORMACI FOLIKULÁRNÍHO LYMFOMU A AGRESIVITĚ CHRONICKÉ LYMFOCYTÁRNÍ LEUKÉMIE

Investor: Ministerstvo zdravotnictví ČR, ÚLOHA MICRORNA A JEJICH CÍLOVÝCH MOLEKUL V TRANSFORMACI FOLIKULÁRNÍHO LYMFOMU A AGRESIVITĚ CHRONICKÉ LYMFOCYTÁRNÍ LEUKÉMIE

802644, interní kód MU

Název: Signaling propensity in the microenvironment of B cell chronic lymphocytic leukemia (Akronym: LeukemiaEnviron)

Investor: Evropská unie, Signaling propensity in the microenvironment of B cell chronic lymphocytic leukemia, ERC (Excellent Science)

90132, velká výzkumná infrastruktura

Název: NCMG II

Přiložené soubory

miR-29_modulates_CD40_signaling_in_chronic_lymphocytic.pdf

Citovat

SHARMA, Sonali; Gabriela MLADONICKÁ PAVLASOVÁ; Václav ŠEDA; Kateřina AMRUZ ČERNÁ; Eva VOJÁČKOVÁ; Daniel FILIP; Laura ONDRIŠOVÁ; Veronika ŠANDOVÁ; Lenka KOŠŤÁLOVÁ; Pedro FARIA ZENI; Marek BORSKÝ; Jan OPPELT; Květoslava LIŠKOVÁ; Leoš KŘEN; Andrea JANÍKOVÁ; Šárka POSPÍŠILOVÁ; Stacey M. FERNANDES; Medhat SHEHATA; Laura Z. RASSENTI; Ulrich JAEGER; Michael DOUBEK; Matthew S. DAVIDS; Jennifer R. BROWN; Jiří MAYER; Thomas J. KIPPS a Marek MRÁZ. miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: an Axis Affected by BCR inhibitors. Blood. Washington, DC: American Society of Hematology, 2021, roč. 137, č. 18, s. 2481-2494. ISSN 0006-4971. Dostupné z: https://doi.org/10.1182/blood.2020005627.

@article{1710496,
   author = {Sharma, Sonali and Mladonická Pavlasová, Gabriela and Šeda, Václav and Amruz Černá, Kateřina and Vojáčková, Eva and Filip, Daniel and Ondrišová, Laura and Šandová, Veronika and Košťálová, Lenka and Faria Zeni, Pedro and Borský, Marek and Oppelt, Jan and Lišková, Květoslava and Křen, Leoš and Janíková, Andrea and Pospíšilová, Šárka and Fernandes, Stacey M. and Shehata, Medhat and Rassenti, Laura Z. and Jaeger, Ulrich and Doubek, Michael and Davids, Matthew S. and Brown, Jennifer R. and Mayer, Jiří and Kipps, Thomas J. and Mráz, Marek},
   article_location = {Washington, DC},
   article_number = {18},
   doi = {https://doi.org/10.1182/blood.2020005627},
   keywords = {MYC; miR-29; TRAF4; BCR signaling; BCR inhibitor},
   language = {eng},
   issn = {0006-4971},
   journal = {Blood},
   title = {miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: an Axis Affected by BCR inhibitors},
   url = {https://doi.org/10.1182/blood.2020005627},
   volume = {137},
   year = {2021}
}

TY  - JOUR
ID  - 1710496
AU  - Sharma, Sonali - Mladonická Pavlasová, Gabriela - Šeda, Václav - Amruz Černá, Kateřina - Vojáčková, Eva - Filip, Daniel - Ondrišová, Laura - Šandová, Veronika - Košťálová, Lenka - Faria Zeni, Pedro - Borský, Marek - Oppelt, Jan - Lišková, Květoslava - Křen, Leoš - Janíková, Andrea - Pospíšilová, Šárka - Fernandes, Stacey M. - Shehata, Medhat - Rassenti, Laura Z. - Jaeger, Ulrich - Doubek, Michael - Davids, Matthew S. - Brown, Jennifer R. - Mayer, Jiří - Kipps, Thomas J. - Mráz, Marek
PY  - 2021
TI  - miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: an Axis Affected by BCR inhibitors
JF  - Blood
VL  - 137
IS  - 18
SP  - 2481-2494
EP  - 2481-2494
PB  - American Society of Hematology
SN  - 00064971
KW  - MYC
KW  - miR-29
KW  - TRAF4
KW  - BCR signaling
KW  - BCR inhibitor
UR  - https://doi.org/10.1182/blood.2020005627
L2  - https://doi.org/10.1182/blood.2020005627
N2  - B cell receptor (BCR) signaling and T cell interactions play a pivotal role in chronic lymphocytic leukemia (CLL) pathogenesis and disease aggressiveness. CLL cells can utilize microRNAs (miRNAs) and their targets to modulate microenvironmental interactions in the lymph node niches. To identify miRNA expression changes in the CLL microenvironment, we performed complex profiling of short non-coding RNAs in this context by comparing CXCR4/CD5 intraclonal cell subpopulations (CXCR4dimCD5bright vs. CXCR4brightCD5dim cells). This identified dozens of differentially expressed miRNAs including several that have previously been shown to modulate BCR signaling (miR-155, miR-150, and miR-22), but also other candidates for a role in microenvironmental interactions. Notably, all three miR-29 family members (miR-29a, miR-29b, miR-29c) were consistently down-modulated in the immune niches, and lower miR-29(a/b/c) levels associated with an increased relative responsiveness of CLL cells to BCR ligation, and significantly shorter overall survival of CLL patients. We identified Tumor-Necrosis Factor Receptor-Associated Factor 4 (TRAF4) as a novel direct target of miR-29s and revealed that higher TRAF4 levels increase CLL responsiveness to CD40 activation and downstream NFkB signaling. In CLL, BCR-represses miR-29 expression via MYC, allowing for concurrent TRAF4 upregulation and stronger CD40-NFkB signaling. This regulatory loop is disrupted by "BCR inhibitors" (BTK inhibitor ibrutinib or PI3K inhibitor idelalisib). In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling/T-cell interactions in a CLL microenvironment and described a novel miR-29-TRAF4-CD40 signaling axis modulated by the BCR activity.
ER  -

SHARMA, Sonali; Gabriela MLADONICKÁ PAVLASOVÁ; Václav ŠEDA; Kateřina AMRUZ ČERNÁ; Eva VOJÁČKOVÁ; Daniel FILIP; Laura ONDRIŠOVÁ; Veronika ŠANDOVÁ; Lenka KOŠŤÁLOVÁ; Pedro FARIA ZENI; Marek BORSKÝ; Jan OPPELT; Květoslava LIŠKOVÁ; Leoš KŘEN; Andrea JANÍKOVÁ; Šárka POSPÍŠILOVÁ; Stacey M. FERNANDES; Medhat SHEHATA; Laura Z. RASSENTI; Ulrich JAEGER; Michael DOUBEK; Matthew S. DAVIDS; Jennifer R. BROWN; Jiří MAYER; Thomas J. KIPPS a Marek MRÁZ. miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: an Axis Affected by BCR inhibitors. \textit{Blood}. Washington, DC: American Society of Hematology, 2021, roč.~137, č.~18, s.~2481-2494. ISSN~0006-4971. Dostupné z: https://doi.org/10.1182/blood.2020005627.

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