mir-29 influences CD40 signaling in chronic lymphocytic leukemia (CLL)

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F20%3A00073228" target="_blank" >RIV/65269705:_____/20:00073228 - isvavai.cz</a>

Výsledek na webu

<a href="https://library.ehaweb.org/eha/2020/eha25th/294972/sonali.sharma.mir-29.influences.cd40.signaling.in.chronic.lymphocytic.leukemia.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D2%2Asearch%3Dhorizon" target="_blank" >https://library.ehaweb.org/eha/2020/eha25th/294972/sonali.sharma.mir-29.influences.cd40.signaling.in.chronic.lymphocytic.leukemia.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D2%2Asearch%3Dhorizon</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

mir-29 influences CD40 signaling in chronic lymphocytic leukemia (CLL)

Popis výsledku v původním jazyce

B cell receptor (BCR) signaling and T cell interactions play a pivotal role in CLL pathogenesis. We and other have previously shown that microRNAs (miRNAs) can regulate BCR signaling in CLL; however, it is unknown if miRNAs are involved in modulating T cell interactions in CLL. Aims: We aimed to identify miRNAs differentially expressed in the CLL microenvironment and to describe the fuction of miR-29 in this context. We performed profiling of short non-coding RNAs (miRNA-seq, Illumina) in the context of microenvironmental interactions by comparing CXCR4/CD5 intraclonal cell subpopulations (CXCR4[dim] CD5[bright] vs. CXCR4[bright] CD5[dim] cells), and studied selected miRNAs by in vitro and in vivo technics. Analysis of CXCR4/CD5 subpopulations 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/b/c) were consistently down-modulated in the immune niches (~2-fold, P&lt;0.001). We further identified a Tumor-Necrosis Factor Receptor-Associated Factor (TRAF) family member as a novel direct target of all miR-29s and revealed that higher TRAF levels increase CLL responsiveness to CD40 activation and downstream NFkB signaling. We have further shown that BCR activation in CLL cells (by anti-IgM) leads to MYC-dependent repression of miR-29, and a subsequent increase in TRAF levels. This shows that BCR signaling acts to coordinate increased CLL cells&apos; responsiveness to the CD40 ligand provided by T cells by modulating miR-29-TRAF axis. This also provides potential mechanisms for the observed concurrent synchronous activation of both BCR and CD40, which is required to induce entry of B cells into the cell cycle (Luo W et al., Immunity, 2018). In a large CLL cohort (n=100), lower miR-29(a/b/c) levels and higher TRAF levels associated with significantly higher responsiveness to BCR crosslinking (assessed as calcium flux after anti-IgM [10 ug/ml]) and shorter overall survival (miR-29a HR: 3.1, CI: 1.3-7.4; miR-29b HR: 3.6, CI: 1.3-10.20; miR-29c HR: 3.4, CI: 1.4-8.3; TRAF: HR: 2.4, CI: 1.2-4.9; all P&lt;0.05). We have also shown that BCR inhibitors ibrutinib or idelalisib (as single agents) lead in vivo to lower MYC levels and significant miR-29 upregulation, while its target, TRAF, is repressed. The CLL cells obtained from patients on ibrutinib therapy are less responsive (P&lt;0.001) to CD40 ligation when compared to paired samples from the same patient obtained before therapy (n=10 pairs). This suggests that the disruption of the miR-29-TRAF regulatory loop by &quot;BCR inhibitors&quot; (ibrutinib/idelalisib) has an in vivo relevance. In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling/T-cell interactions in the CLL microenvironment. We describe a novel miR-29-TRAF-CD40 signaling axis modulated by BCR activity and disrupted by BCR inhibitors such as ibrutinib or idelalisib.

Název v anglickém jazyce

mir-29 influences CD40 signaling in chronic lymphocytic leukemia (CLL)

Popis výsledku anglicky

B cell receptor (BCR) signaling and T cell interactions play a pivotal role in CLL pathogenesis. We and other have previously shown that microRNAs (miRNAs) can regulate BCR signaling in CLL; however, it is unknown if miRNAs are involved in modulating T cell interactions in CLL. Aims: We aimed to identify miRNAs differentially expressed in the CLL microenvironment and to describe the fuction of miR-29 in this context. We performed profiling of short non-coding RNAs (miRNA-seq, Illumina) in the context of microenvironmental interactions by comparing CXCR4/CD5 intraclonal cell subpopulations (CXCR4[dim] CD5[bright] vs. CXCR4[bright] CD5[dim] cells), and studied selected miRNAs by in vitro and in vivo technics. Analysis of CXCR4/CD5 subpopulations 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/b/c) were consistently down-modulated in the immune niches (~2-fold, P&lt;0.001). We further identified a Tumor-Necrosis Factor Receptor-Associated Factor (TRAF) family member as a novel direct target of all miR-29s and revealed that higher TRAF levels increase CLL responsiveness to CD40 activation and downstream NFkB signaling. We have further shown that BCR activation in CLL cells (by anti-IgM) leads to MYC-dependent repression of miR-29, and a subsequent increase in TRAF levels. This shows that BCR signaling acts to coordinate increased CLL cells&apos; responsiveness to the CD40 ligand provided by T cells by modulating miR-29-TRAF axis. This also provides potential mechanisms for the observed concurrent synchronous activation of both BCR and CD40, which is required to induce entry of B cells into the cell cycle (Luo W et al., Immunity, 2018). In a large CLL cohort (n=100), lower miR-29(a/b/c) levels and higher TRAF levels associated with significantly higher responsiveness to BCR crosslinking (assessed as calcium flux after anti-IgM [10 ug/ml]) and shorter overall survival (miR-29a HR: 3.1, CI: 1.3-7.4; miR-29b HR: 3.6, CI: 1.3-10.20; miR-29c HR: 3.4, CI: 1.4-8.3; TRAF: HR: 2.4, CI: 1.2-4.9; all P&lt;0.05). We have also shown that BCR inhibitors ibrutinib or idelalisib (as single agents) lead in vivo to lower MYC levels and significant miR-29 upregulation, while its target, TRAF, is repressed. The CLL cells obtained from patients on ibrutinib therapy are less responsive (P&lt;0.001) to CD40 ligation when compared to paired samples from the same patient obtained before therapy (n=10 pairs). This suggests that the disruption of the miR-29-TRAF regulatory loop by &quot;BCR inhibitors&quot; (ibrutinib/idelalisib) has an in vivo relevance. In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling/T-cell interactions in the CLL microenvironment. We describe a novel miR-29-TRAF-CD40 signaling axis modulated by BCR activity and disrupted by BCR inhibitors such as ibrutinib or idelalisib.

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)

Rok uplatnění

2020

Kód důvěrnosti údajů

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