2020
Regulation of BCR signaling during therapy in chronic lymphocytic leukemia.
KOŠŤÁLOVÁ, Lenka, Václav ŠEDA, Laura ONDRIŠOVÁ, Eva VOJÁČKOVÁ, Daniel FILIP et. al.Základní údaje
Originální název
Regulation of BCR signaling during therapy in chronic lymphocytic leukemia.
Autoři
KOŠŤÁLOVÁ, Lenka (203 Česká republika, domácí), Václav ŠEDA (203 Česká republika, domácí), Laura ONDRIŠOVÁ (703 Slovensko, domácí), Eva VOJÁČKOVÁ (203 Česká republika, domácí), Daniel FILIP (703 Slovensko, domácí), Veronika ŠANDOVÁ (203 Česká republika, domácí), Sonali SHARMA (356 Indie, domácí) a Marek MRÁZ (203 Česká republika, domácí)
Vydání
XIX. Interdisciplinary Meeting of Young Biologists, Biochemists and Chemists. Milovy, 2020
Další údaje
Jazyk
angličtina
Typ výsledku
Konferenční abstrakt
Obor
30204 Oncology
Stát vydavatele
Česká republika
Utajení
není předmětem státního či obchodního tajemství
Odkazy
Kód RIV
RIV/00216224:14740/20:00117951
Organizační jednotka
Středoevropský technologický institut
Klíčová slova anglicky
BCR SIGNALING
Štítky
Změněno: 18. 3. 2021 20:09, Mgr. Pavla Foltynová, Ph.D.
Anotace
V originále
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults in western countries. It is characterized by an accumulation of malignant B lymphocytes in blood and lymphatic tissues. CLL cells are highly dependent on interactions with the tissue microenvironment for their survival and proliferation. These interactions lead to the activation of several pro-survival pathways, especially B cell receptor (BCR) signaling. Small molecule inhibitors including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib targeting BCR signaling have been recently approved and show remarkable clinical activity in CLL1. We and others have shown that ibrutinib does not affect only the BCR signaling pathway, but also the cell-cell interactions and chemokine signaling in the microenvironment2. Notably, ibrutinib therapy only leads to a relatively slow decrease in CLL cell numbers with a lymphocytosis persisting for several months, and this could contribute to the devel opment of a resistant disease. To describe the mechanisms contributing to CLL survival in peripheral blood we have performed gene expression profiling (N=14 paired samples; RNAseq, Illumina) of primary CLL samples obtained from CLL patients before and during treatment with ibrutinib. Subsequently, we have selected candidate genes that could be potentially responsible for the early adaptation to ibrutinib treatment. We focused on the role of protein tyrosine phosphatases (PTPs) and adaptor molecules that in normal B cells are responsible for the negative regulation of BCR-signaling. We have shown that after ibrutinib treatment in vitro and also in vivo the expression of several PTPs (P<0.001) is downmodulated suggesting that CLL cells tend to maintain their BCR activity despite inhibition of BTK kinase. We demonstrated by siRNA-based silencing that repression of a particular PTP positively affects BCR signaling and maintains a high basal activity of down-stream pro-survival k inases irrespectively of antigen-binding. Altogether, the downregulation of PTP could contribute to the survival of CLL cells in peripheral blood by decreasing the threshold for tonic or antigen-induced BCR activation and this might be of relevance for adaptation to BCR inhibitor therapy in CLL.
Návaznosti
| LQ1601, projekt VaV |
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| MUNI/A/1395/2019, interní kód MU |
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| NV18-03-00054, projekt VaV |
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| 802644, interní kód MU |
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