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Effect of clinically observed BTK mutations on gene expression during cell proliferation and differentiation in TMD8 cells

ABSTRACT: To investagate the clinically observed BTK C481S, C481F, C481Y and C481R mutations in the regulation of B cell receptor signaling, we extablished TMD8 cells expressing BTK C481S, C481F, C481Y and C481R in which endogenous BTK was inactivated by ibrutinib. We then performed gene expression profiling analysis using data obtained from RNA-seq of 20 different cells after DMSO or 10 nM ibrutinib treatment from two indenpendent experiments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207322 | GEO | 2022/11/29

REPOSITORIES: GEO

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RNA-Seq to Explore 2-Sulfonylpyrimidine Warheads as Acrylamide Surrogates for Targeted Covalent Inhibition of BTK in Diffuse Large B Cell (DLBCL) Cell Line TMD8

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Gene expression data of parental and ibrutinib-resistant TMD8 cells.

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RNA-Seq for a differential gene expression bewteen KLHL14 wild-type(+/+) and KLHL14 knockout(-/-) TMD8 ABC-DLBCL cell line upon treatment with a BTK inhibitor, ibrutinib

Project description:The goal of this study is to examine gene expression changes in TMD8 KLHL14(+/+) or TMD8 KLHL14(-/-) cells during ibrutinib treatment. The samples have 35 to 63 million pass filter reads with more than 92% of bases above the quality score of Q30.The average mapping rate of all samples is 95%. Unique alignment is above 86%. There are 3.65 to 6.25% unmapped reads.The mapping statistics are calculated using Picard software. The samples have between 0.86-1.29% ribosomal bases. Percent coding bases are between 58-62%. Percent UTR bases are 27-31%, and mRNA bases are between 87-90% for all the samples. We show that TMD8 KLHL14(-/-) cells have less down-regulation of NF-kB signatures and IL10/JAK1/STAT3 signatures upon ibrutinib treatment when compared to TMD8 KLHL14(+/+) cells.

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Project description:Effect of clinically observed BTK mutations on gene expression during cell proliferation and differentiation in TMD8 cells

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2022-03-19 | GSE198992 | GEO

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Project description:Inhibition of Bruton’s tyrosine kinase (BTK) has proven to be highly effective in the treatment of B-cell malignancies such as chronic lymphocytic leukemia (CLL), autoimmune disorders and multiple sclerosis. Since the approval of the first BTK inhibitor (BTKi), Ibrutinib, several other inhibitors including Acalabrutinib, Zanubrutinib, Tirabrutinib and Pirtobrutinib have been clinically approved. All are covalent active site inhibitors, with the exception of the reversible active site inhibitor Pirtobrutinib. The large number of available inhibitors for the BTK target creates challenges in choosing the most appropriate BTKi for treatment. Side-by-side comparisons in CLL have shown that different inhibitors may differ in their treatment efficacy. Moreover, the nature of the resistance mutations that arise in patients appears to depend on the specific BTKi administered. We have previously shown that Ibrutinib binding to the kinase active site causes unanticipated long-range effects on the global conformation of BTK (Joseph, R.E., et al., 2020, https://doi.org/10.7554/eLife.60470). Here we show that binding of each of the five approved BTKi to the kinase active site brings about distinct allosteric changes that alter the conformational equilibrium of full-length BTK. Additionally, we provide an explanation for the resistance mutation bias observed in CLL patients treated with different BTKi and characterize the mechanism of action of two common resistance mutations: BTK T474I and L528W.

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Expression data from DLBCL tumor biopsies

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