Mechanisms of leukemia cell adaptation to targeted therapy in chronic lymphocytic leukemia

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F19%3A00071792" target="_blank" >RIV/65269705:_____/19:00071792 - isvavai.cz</a>

Výsledek na webu

<a href="http://www.ccsss.cz/index.php/ccsss/issue/viewIssue/19/32" target="_blank" >http://www.ccsss.cz/index.php/ccsss/issue/viewIssue/19/32</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Mechanisms of leukemia cell adaptation to targeted therapy in chronic lymphocytic leukemia

Popis výsledku v původním jazyce

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the western world. Malignant B lymphocytes are accumulating in bone marrow, blood and lymphatic tissues. The immune niche microenvironment of the CLL cells plays an important role in the disease as major prosurvival pathways are activated here, especially B-cell receptor (BCR) signalling. Recently, a novel efficient therapy has been developed for CLL targeting microenvironmental interactions. Ibrutinib is a small-molecule inhibitor of an essential BCR-associated Bruton tyrosine kinase (BTK). We have previously shown that ibrutinib interferes not only with BCR signalling but also with migration of CLL cells to the immune microenvironment1 which leads to a gradual regression of the disease during several months. However, ibrutinib therapy does not lead to a cure, and the slow apoptosis of CLL cells exposed to ibrutinib in vivo allows the malignant cells to adapt and eventually become resistant to therapy. To decipher the mechanisms that allow CLL cells to survive during ibrutinib treatment we have performed gene expression profiling (RNAseq, Illumina) of CLL samples obtained from CLL patients pre- and post-treated with ibrutinib (n=22, 11 pairs). This revealed a number of genes that are influenced by BCR-inhibition in vivo (N=1305, P-adjusted &lt;0.01). The ibrutinib treatment influenced activity of pathways, such as MAPK signalling pathway (P=5x10-12), focal adhesion (P=5x10-8), PI3K signalling pathway (P=1.6x10-3) or autophagy (P=1.6x10-2), and some of this might compensate for the inhibition of BTK. Next, we selected potential candidate molecules that could be responsible for the early adaptation/relative resistance to the drug and we have mechanistically shown in vitro that up-regulation and activation of a PI3K-signalling regulatory molecule allows B cells to become relatively resistant to ibrutinib. Currently, this is being further validated with more primary samples from patients. Altogether, we provide molecular evidence for a novel combinatorial therapeutic strategy with ibrutinib, which might be sufficient to achieve a deep clinical response in CLL without the use of chemo-therapy.

Název v anglickém jazyce

Mechanisms of leukemia cell adaptation to targeted therapy in chronic lymphocytic leukemia

Popis výsledku anglicky

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the western world. Malignant B lymphocytes are accumulating in bone marrow, blood and lymphatic tissues. The immune niche microenvironment of the CLL cells plays an important role in the disease as major prosurvival pathways are activated here, especially B-cell receptor (BCR) signalling. Recently, a novel efficient therapy has been developed for CLL targeting microenvironmental interactions. Ibrutinib is a small-molecule inhibitor of an essential BCR-associated Bruton tyrosine kinase (BTK). We have previously shown that ibrutinib interferes not only with BCR signalling but also with migration of CLL cells to the immune microenvironment1 which leads to a gradual regression of the disease during several months. However, ibrutinib therapy does not lead to a cure, and the slow apoptosis of CLL cells exposed to ibrutinib in vivo allows the malignant cells to adapt and eventually become resistant to therapy. To decipher the mechanisms that allow CLL cells to survive during ibrutinib treatment we have performed gene expression profiling (RNAseq, Illumina) of CLL samples obtained from CLL patients pre- and post-treated with ibrutinib (n=22, 11 pairs). This revealed a number of genes that are influenced by BCR-inhibition in vivo (N=1305, P-adjusted &lt;0.01). The ibrutinib treatment influenced activity of pathways, such as MAPK signalling pathway (P=5x10-12), focal adhesion (P=5x10-8), PI3K signalling pathway (P=1.6x10-3) or autophagy (P=1.6x10-2), and some of this might compensate for the inhibition of BTK. Next, we selected potential candidate molecules that could be responsible for the early adaptation/relative resistance to the drug and we have mechanistically shown in vitro that up-regulation and activation of a PI3K-signalling regulatory molecule allows B cells to become relatively resistant to ibrutinib. Currently, this is being further validated with more primary samples from patients. Altogether, we provide molecular evidence for a novel combinatorial therapeutic strategy with ibrutinib, which might be sufficient to achieve a deep clinical response in CLL without the use of chemo-therapy.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10606 - Microbiology

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