Molecular response of chronic lymphocytic leukemia cells to targeted therapy.
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| Year of publication | 2023 |
| Type | Conference abstract |
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| Description | Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western world. The characteristic symptom of the disease is the accumulation of malignant cells in lymphoid organs and blood. The microenvironment of lymphatic tissues provides CLL cells with various pro-survival stimuli that may impair therapy efficiency. Small-molecule inhibitors targeting microenviron mental interactions represent a novel therapeutic approach. BTK inhibitor ibrutinib and PI3K inhibitor idelalisib disrupt B-cell receptor signaling (BCR), and CLL cell adhesion, CLL T cell interactions and other microenvironmental stimuli. This leads to unprecedented clinical efficacy in CLL; however, some patients develop resistance to these inhibitors. We hypothesize that the resistance mediated by mutations in targeted kinases is preceded by a signaling adaptation that allows prolonged survival of CLL cells during therapy. Gene expression profiling (RNAseq, Illumina) of CLL samples obtained from patients pre- and post-treatment with ibrutinib (n=22, 11 pairs) or idelalisib (n=18, 9 pairs) and subsequent in vitro experiments on primary CLL cells and CLL-derived cell line MEC1 allowed us to define a specific transcription factor that plays a role in adaptation of CLL cells to BCR inhibitor therapy. Inhibition of the transcription factor together with ibrutinib or idelalisib decreased CLL cells’ viability and proliferation. To further uncover the role of this transcription factor in CLL, we performed Cut&Run assay, an alternative to ChIPseq, in the MEC1 cell line, to characterize genes directly regulated by this transcription factor. Apart from the regulation of the BCR signaling pathway, we noticed its potential in response to other drugs such as the BH3 mimetic (BCL2 inhibitor) venetoclax that has been recently approved for CLL therapy. Altogether, we thoroughly describe particular changes in CLL transcriptome, that provide increase in survival of leukemic cells during the BCR inhibitors therapy in both primary CLL cells and cell lines. Based on these results, we further suggest a rational combinatorial treatment of ibrutinib/idelalisib with an inhibitor targeting the transcription factor as a potential therapeutic strategy to eliminate mechanism of adaptation to BCR inhibitors. |
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