Multi-omics exploration of microenvironmental changes during BTK covalent inhibition in chronic lymphocytic leukemia
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ABSTRACT:
PROVIDER: PRJNA1071569 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27819539_1.fastq.gz | Fastqsanger.gz | |||
| SRR27819539_2.fastq.gz | Fastqsanger.gz | |||
| SRR27819540_1.fastq.gz | Fastqsanger.gz | |||
| SRR27819540_2.fastq.gz | Fastqsanger.gz | |||
| SRR27819541_1.fastq.gz | Fastqsanger.gz |
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Project description:Continuous treatment with ibrutinib not only exerts tumor control but also enhances T cell function in patients with chronic lymphocytic leukemia (CLL). We conducted longitudinal multiomics analyses in samples from CLL patients receiving ibrutinib upfront to identify potential adaptive mechanisms to Bruton Tyrosine Kinase (BTK) inhibition during the first 12 months of continuous therapy. Wefound that in T cells, ibrutinib reduced the expression of exhaustion markers, the proportion of Tregs and Tfh cells, as well as expression of genes related to activation, proliferation, differentiation, and metabolism. In CLL cells, we observed a downregulation of immunosuppression, adhesion, and migration mechanisms. Adaptation at molecular level, characterized by an increase in cancer cell fraction of CLL cells with mutated driver genes, was observed in around half of the patients. Interestingly, BTK C481S mutations were detected as early as after 6 months of treatment, particularly enriched in subsets of malignant cells retaining migrative capacity. These CLL cells with potential migrative capacity under ibrutinib also exhibited a distinct transcriptomic profile including upregulation of mTOR-AKT and Myc pathways. We identified high expression of TMBIM6 as a potential novel independent poor prognostic factor. Of note, BIA, a TMBIM6 antagonist, induced CLL cell apoptosis and synergized with ibrutinib. In summary, our comprehensive multi-omics analysis of CLL patients undergoing ibrutinib therapy has unveiled early immunomodulatory effects on T cells and adaptative mechanisms in CLL cells. These findings can contribute to the identification of resistance mechanisms and the discovery of novel therapeutic targets.
2024-02-07 | GSE254718 | GEO
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.
2024-12-04 | PXD047865 | Pride
Project description:Bruton Tyrosine Kinase (BTK) plays an essential role in signal transduction downstream of cell surface receptors on B lymphocytes, including the B-cell receptor (BCR), a key driver of several sub-types of human B-cell lymphoma and leukaemia. As such, BTK inhibitors have proven to be effective therapies for B-cell malignancies, most notably Ibrutinib. Targeted covalent inhibitors (TCIs) directing cysteine typically rely on a narrow set of electrophilic “warheads”. Michael acceptors remain at the forefront of TCI design strategies, yet have variable stability and selectivity under physiological conditions. Our RNA-Seq experiments were performed on TMD8 cells that had been cultured for 8 hours with DMSO, ibrutinib or 4 chemical constructs that we describe in Moraru et al. (2024), resulting in a total of 18 libraries. Our data show that the 2-sulfonylpyrimidine motif is an effective replacement for the acrylamide warhead of Ibrutinib.
2024-08-29 | E-MTAB-14363 | biostudies-arrayexpress
Project description:Bruton Tyrosine Kinase (BTK) is a crucial target for anticancer, anti-inflammatory, and antiviral therapies. BTK inhibitors (BTKis) have revolutionized the therapeutic options for B-cell malignancies, including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and small lymphocytic lymphoma. Despite the therapeutic efficacy achieved with BTKis, some patients develop relapse and drug resistance. Different new approaches offer an alternative way to prevent or overcome the resistance: by targeting bypass mechanisms by combination therapies;temporal sequencing of therapies;chimeric antigen receptor-modified T (CAR-T) cell therapy;real-time monitoring of patient response; next-generation BTKis (ngBTKis). Above all, ngBTKis and combined treatment are proposed as strategies more effective and less toxic, to improve disease management and patient survival. Epigenomics of B-cell malignancies may explain the intraclonal diversification and help elucidating the reason of emerging relapse and treatment refractoriness/resistance. We identified the first next-generation, selective, reversible, non-covalent BTK-epigenetic inhibitor (BTK-epi-inhibitor) capable of downregulating BTK at both the transcriptional and enzymatic levels.To characterize this molecule, we employed a comprehensive and integrative experimental approach, encompassing genomic, epigenomic, transcriptional, and on-target analyses. We investigated the molecular and functional mechanisms underlying the activity of UVI5008, while also evaluating its therapeutic efficacy, toxicity, pharmacokinetics, and safety profile. These studies were conducted through a combination of in vitro (cell culture), ex vivo, and in vivo (animal model) experiments, aiming to minimize side effects and off-target toxicity. Importantly, we demonstrated that UVI5008 inhibits both wild-type BTK and the C481S mutant isoform—a key mutation associated with resistance to first-generation BTK inhibitors—across in silico, ex vivo, and in vivo models of chronic lymphocytic leukemia (CLL) and B-cell lymphoma. Treatment with UVI5008 led to a significant increase in cell death, accompanied by a reduction in BTK protein levels, its phosphorylation, and downstream signaling activity. Taken together, these data highlight the novelty, potency, and clinical relevance of UVI5008 as a new therapeutic strategy for BTK-driven malignancies, especially in relapsed/refractory (R/R) CLL and B-cell lymphoma, where current therapies often fail.
2026-03-11 | GSE295723 | GEO
Project description:Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in chronic lymphocytic leukemia (CLL). Target occupancy has been measured as a pharmacodynamic parameter in clinical studies of covalent BTK inhibitors. However, the kinetics of BTK turnover, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remains undefined. This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily or 200 mg once daily in 48 patients with relapsed/refractory or high-risk treatment naïve CLL. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% CI 78.9%, 99.9%) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI 70.0%, 97.8%) with twice daily dosing and an ORR of 79.2% (95% CI 57.9%, 92.9%) and an estimated PFS rate at 24 months of 87.2% (95% CI 57.2%, 96.7%) with once daily dosing. BTK resynthesis was faster in CLL than in healthy volunteers. Twice daily dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared to once daily dosing. Additional follow-up is required to address the impact of dosing schedule and BTK occupancy on long-term clinical outcomes.
2020-04-07 | GSE136634 | GEO
Project description:Bruton’s tyrosine kinase (BTK) is targeted in the treatment of B-cell disorders including leukemias and lymphomas. Currently approved BTK inhibitors, including Ibrutinib, a first-in-class covalent inhibitor of BTK, bind directly to the kinase active site. While effective at blocking the catalytic activity of BTK, consequences of drug binding on the global conformation of full-length BTK are unknown. Here we uncover a range of conformational effects in full-length BTK induced by a panel of active site inhibitors, including unexpected shifts in the conformational equilibria of the regulatory domains. Additionally, we find that a remote Ibrutinib resistance mutation, T316A in the BTK SH2 domain, drives spurious BTK activity by destabilizing the compact autoinhibitory conformation of full-length BTK, shifting the conformational ensemble away from the autoinhibited form. Future development of BTK inhibitors will need to consider long-range allosteric consequences of inhibitor binding, including the emerging application of these BTK inhibitors in treating COVID-19.
2020-11-25 | PXD020029 | Pride
Project description:2p Gain-Driven REL Overexpression Confers Resistance to BTK Inhibitors in Chronic Lymphocytic Leukemia
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Project description:Defining the acute BTK-loss transcriptional program in CLL using a BTK degrader by RNA-seq
2026-03-11 | GSE319429 | GEO
Project description:Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice autoimmune indications. However, our current knowledge of the role of BTK in immune competence has been gathered in the context of genetic inactivation of btk in both mice and man. Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice. We implicate BTK in tonic BCR signaling, demonstrate dependence of the T3 B cell subset and IgM surface expression on BTK activity, and find that B1 cells survive and function independently of BTK. While BTK inhibition does not impact humoral memory survival, antigen-driven clonal expansion of memory B cells and antibody secreting cell generation are inhibited. These data define the role of BTK in the mature immune system and mechanistically predict the clinical phenotype of BTK inhibition. We used Affymetrix genechips to profile the transcriptional changes downstream of BTK inhibition after in vivo B-cell activation by anti-IgD Mice were injected with the novel BTK inhibitor PF-303 2 hours prior to anti-IgD mediated in vivo B-cell activation; B-cells where harvested 2 hours after anti-IgD activation and RNA isolated.
2014-08-01 | E-GEOD-56483 | biostudies-arrayexpress
Project description:Bruton's tyrosine kinase (Btk) is important for B lymphocyte development. To identify genes that are differentially expressed in primary B cells lacking functional Btk, splenocytes from X-linked immunodeficiency (Xid), Btk knockout (KO) and immunocompetent CBA mice, were used in microarrays containing more than 12,000 genes and expressed sequence tags (ESTs). We found 4515 transcripts expressed in duplicate experiments in all three strains. Out of these, 38 were differentially expressed genes (21 up-regulated >2 fold and 17 down-regulated <-2 fold) between CBA and Btk defective mice. Ten out of these genes were selected and quantitative Real-Time PCR was conducted for validation and further investigation. Real-Time experiments correlated nicely with the microarray data. No definitive phenotypic difference has previously been reported between Xid and Btk KO mice. We found 7 genes, whose expression differed (>2 fold) between the two strains. Moreover, when the 38 genes, which differed between immunocompetent CBA and Btk defective mice were ranked according to fold-increase, the levels in Btk KO mice were significantly more altered. This suggests that the defect in Btk KO mice is more severe and demonstrates that the mutant Btk protein in Xid mice does not generally function as dominant negative form. Experiment Overall Design: 6 Affymetrix U74Av2 GeneChip arrays was run. Three initially with CBA, Xid and Btk KO mice and then additional three chips with new RNA preperations from new CBA, Xid and Btk KO mice.
2007-08-31 | E-GEOD-2826 | biostudies-arrayexpress