The Role of Long Non-coding RNAs in the BCR-mediated Activation of Malignant B Cells

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F21%3A00075092" target="_blank" >RIV/65269705:_____/21:00075092 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.ceitec.eu/ceitec-phd-conference-2021/a3988" target="_blank" >https://www.ceitec.eu/ceitec-phd-conference-2021/a3988</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

The Role of Long Non-coding RNAs in the BCR-mediated Activation of Malignant B Cells

Popis výsledku v původním jazyce

The B cell receptor (BCR) is responsible for triggering the canonical signalling to mediate B cell activation and its transduction is tuned by a network of kinases and phosphatases capable to dictate B cell fate. Remarkably, B cell malignancies frequently exhibit a gene expression profile of constitutive BCR activation. The essential role of BCR signalling in B cell malignancies is highlighted by the major success of single-agent BCR inhibitor treatment in chronic lymphocytic leukaemia (CLL) patients. Dysregulation of BCR signalling in CLL cells is the major drive force for proliferation and tumour maintenance, partially mediated by non-coding RNAs. MicroRNAs (miRNAs), such as miR-155, were described to be directly involved in the regulation of the BCR pathway targeting kinases and phosphatases, or even the downstream effectors of the BCR pathway. Although microRNAs play an essential role in regulating BCR pathway, it is unclear if long non-coding RNAs (lncRNAs) are involved in BCR signalling. LncRNAs can serve as a sponge for miRNAs, as a scaffold for proteins, as regulators for transcription factors, or even participate in signal transduction. LncRNAs were shown to be involved in several lymphocyte pathways and based on this rationale, we questioned whether any lncRNAs could be involved in the BCR pathway. To address this question, we investigated differentially expressed lncRNAs from CLL patients treated with BCR inhibitors (Ibrutinib and Idelalisib) and we cross-validated these lncRNAs between high BCR activity (CXCR4dimCD5bright) vs low BCR activity (CXCR4brightCD5dim) in intraclonal CLL cell subpopulations. We found 12 lncRNAs (named lncRNA-BCR1 to lncRNA-BCR12) related to the BCR pathway, including one, which is the host gene for miR-155, and we selected lncRNA-BCR1 for further studies. We hypothesized that lncRNABCR1 is regulated in a BCR-dependent fashion. We confirmed that lncRNA-BCR1 is upregulated upon BCR activation and impaired when treated with BCR inhibitors. In line with this, lncRNA-BCR1 was also downregulated in CLL patients undergoing Ibrutinib therapy. However, a contraintuitive observation was made when we analyzed the expression of this lncRNA in a CLL cohort. CLL patients with high expression of lncRNA-BCR1 have longer survival compared to those with relatively low levels. In order to understand these observations in more detail, we transcriptionally repressed lncRNA-BCR1 using a dCAS9-KRAB system in CLL cell lines. These engineered cell lines will be used for further functional assays to explain the molecular mechanism underlying the BCR activation and its effect on the survival of CLL patients. In summary, we identified lncRNAs potentially participating in the BCRmediated activation of malignant B cells. Our data suggest that lncRNA-BCR1 is involved in the BCR pathway and elucidating this interplay could improve the understanding of the pathogenesis of B cell malignancies.

Název v anglickém jazyce

The Role of Long Non-coding RNAs in the BCR-mediated Activation of Malignant B Cells

Popis výsledku anglicky

The B cell receptor (BCR) is responsible for triggering the canonical signalling to mediate B cell activation and its transduction is tuned by a network of kinases and phosphatases capable to dictate B cell fate. Remarkably, B cell malignancies frequently exhibit a gene expression profile of constitutive BCR activation. The essential role of BCR signalling in B cell malignancies is highlighted by the major success of single-agent BCR inhibitor treatment in chronic lymphocytic leukaemia (CLL) patients. Dysregulation of BCR signalling in CLL cells is the major drive force for proliferation and tumour maintenance, partially mediated by non-coding RNAs. MicroRNAs (miRNAs), such as miR-155, were described to be directly involved in the regulation of the BCR pathway targeting kinases and phosphatases, or even the downstream effectors of the BCR pathway. Although microRNAs play an essential role in regulating BCR pathway, it is unclear if long non-coding RNAs (lncRNAs) are involved in BCR signalling. LncRNAs can serve as a sponge for miRNAs, as a scaffold for proteins, as regulators for transcription factors, or even participate in signal transduction. LncRNAs were shown to be involved in several lymphocyte pathways and based on this rationale, we questioned whether any lncRNAs could be involved in the BCR pathway. To address this question, we investigated differentially expressed lncRNAs from CLL patients treated with BCR inhibitors (Ibrutinib and Idelalisib) and we cross-validated these lncRNAs between high BCR activity (CXCR4dimCD5bright) vs low BCR activity (CXCR4brightCD5dim) in intraclonal CLL cell subpopulations. We found 12 lncRNAs (named lncRNA-BCR1 to lncRNA-BCR12) related to the BCR pathway, including one, which is the host gene for miR-155, and we selected lncRNA-BCR1 for further studies. We hypothesized that lncRNABCR1 is regulated in a BCR-dependent fashion. We confirmed that lncRNA-BCR1 is upregulated upon BCR activation and impaired when treated with BCR inhibitors. In line with this, lncRNA-BCR1 was also downregulated in CLL patients undergoing Ibrutinib therapy. However, a contraintuitive observation was made when we analyzed the expression of this lncRNA in a CLL cohort. CLL patients with high expression of lncRNA-BCR1 have longer survival compared to those with relatively low levels. In order to understand these observations in more detail, we transcriptionally repressed lncRNA-BCR1 using a dCAS9-KRAB system in CLL cell lines. These engineered cell lines will be used for further functional assays to explain the molecular mechanism underlying the BCR activation and its effect on the survival of CLL patients. In summary, we identified lncRNAs potentially participating in the BCRmediated activation of malignant B cells. Our data suggest that lncRNA-BCR1 is involved in the BCR pathway and elucidating this interplay could improve the understanding of the pathogenesis of B cell malignancies.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30205 - Hematology

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

2021

Kód důvěrnosti údajů

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