Similar Datasets
Project description:Defining the acute BTK-loss transcriptional program in CLL using a BTK degrader
| PRJNA1423275 | ENA
Project description:BTK plays a critical role in B cell malignancies survival. BTK inhibitor was successfully used as first line treatment for CLL in clinical. The emerging unmet needs is new segments are needed for ibrutinib R/R patients. The purpose of this study is to investigate genomic changes and signaling pathway differences after CLL cells were treated with BTK inhibitor (ibrutinib) or degrader (NRX0492).
2022-03-19 | GSE198992 | GEO
Project description:RNA sequencting of CLL cells treated by BTK degrader
| PRJNA817799 | ENA
Project description:Inactivating mutations in the NF-kB inhibitor NFKBIE are frequent in chronic lymphocytic leukemia (CLL) and have been associated with accelerated disease progression and inferior responses to chemotherapy. To further understand the role of NFKBIE mutations in CLL, we disrupted by CRISPR/Cas9 editing the NFKBIE gene in CLL cells derived from the Eμ-TCL1 transgenic mouse model and investigated how this will affect CLL growth and response to B cell receptor inhibitor treatment. In vitro and adoptive transfer experiments showed that NFKBIE-mutated cells have a growth advantage over NFKBIE-wild type cells when exposed to microenvironmental signals that activate the canonical NF-kB pathway and can induce alterations within the tumor microenvironment that may allow for escape from immune surveillance, including the expansion of CD8+ T cells with an exhausted phenotype and increased expression of PD-L1 on the malignant B cells. Consistent with these findings, significantly greater expression of the exhaustion markers PD1 and TIGIT was observed on T cells from CLL patients with NFKBIE-mutated compared to NFKBIE-wild type leukemia. In addition, in vitro and in vivo experiments showed that NFKBIE-mutated murine CLL cells are selectively resistant to BTK inhibitor treatment while remaining sensitive to treatment with a PI3K or SYK inhibitor. Reduced sensitivity to BTK inhibitor treatment was also observed in a series of 229 ibrutinib-treated CLL patients showing inferior outcomes for the NFKBIE-mutated cases. These findings provide evidence that NFKBIE-mutated CLL cells reshape and are selected by the tumor microenvironment and may account for suboptimal ibrutinib responses.
2024-01-29 | GSE231799 | 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:Targeted sequencing in ibrutinib treated CLL
| PRJEB44894 | ENA
Project description:Ibrutinib, an irreversible Bruton Tyrosine Kinase (BTK) inhibitor, has revolutionized Chronic Lymphocytic Leukemia (CLL) treatment, but resistances to ibrutinib have emerged in relation or not to BTK mutations. Evolution patterns of CLL before and after ibrutinib therapy are often focused only on leukemic cells but must be investigated in the context of the CLL microenvironment. Single cell RNA-seq and related technologies allow a deeper characterization of cancer and normal cells. We therefore investigated whether ibrutinib treatment drives molecular changes in CLL. Here, we report the monitoring of a CLL patient under ibrutinib treatment using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-Seq) technology. We report that the short clinical relapse of this patient, driven by BTK mutation, is associated with intra-clonal heterogeneity and transcriptional and phenotypical modifications in both B leukemic and immune cells. These results open new therapeutic strategies for ibrutinib-refractory CLL patients.
2020-12-15 | GSE152469 | GEO
Project description:Bulk RNA-seq analysis of Btk-deficient leukemia
| PRJEB41313 | ENA
Project description:We collected three timepoint blood samples from a CLL patient underwent BTK inhibitor treatment. We performed single cell RNA sequencing on these samples to track expression heterogeneity of malignant B-cell populations over time.
2021-10-22 | GSE186150 | GEO
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