Regulation of BCR signaling during therapy in chronic lymphocytic leukemia.
| Autoři | |
|---|---|
| Rok publikování | 2020 |
| Druh | Konferenční abstrakty |
| Fakulta / Pracoviště MU | |
| Citace | |
| Popis | 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. |
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