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RNA sequencting of CLL cells treated by BTK degrader

ABSTRACT: RNA sequencting of CLL cells treated by BTK degrader

PROVIDER: PRJNA817799 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18362975_1.fastq.gz	Fastqsanger.gz
	SRR18362975_2.fastq.gz	Fastqsanger.gz
	SRR18362976_1.fastq.gz	Fastqsanger.gz
	SRR18362976_2.fastq.gz	Fastqsanger.gz
	SRR18362977_1.fastq.gz	Fastqsanger.gz

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RNA sequencting of CLL cells treated by BTK degrader

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

Defining the acute BTK-loss transcriptional program in CLL using a BTK degrader

Project description:Defining the acute BTK-loss transcriptional program in CLL using a BTK degrader by RNA-seq

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Defining the acute BTK-loss transcriptional program in CLL using a BTK degrader

Project description:Defining the acute BTK-loss transcriptional program in CLL using a BTK degrader

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Molecular and Structural Basis of Pan-Resistance to BTK Inhibitors and Degraders

Project description:Early-phase clinical trials of Bruton’s tyrosine kinase (BTK) degraders have demonstrated efficacy in patients with BTK inhibitor-resistant chronic lymphocytic leukemia (CLL). How clinical resistance to BTK degraders arises is unknown. Here we sequenced serial CLL samples from patients enrolled in the phase I trials of zelebrudomide and bexobrutideg and observed recurrent expansion of preexisting BTK A428D mutations at relapse. Unlike previously studied BTK inhibitor resistance mutations, BTK A428D conferred pan-resistance to BTK inhibitors and degraders. In the absence of BTK-directed therapies, however, cells bearing BTK A428D exhibited a competitive disadvantage. A crystal structure of BTK A428D revealed that the mutant aspartate confers broad resistance to ATP-competitive small molecules by obstructing essential drug contacts with the kinase hinge. Combining BTK degraders with venetoclax mitigated expansion of BTK A428D. These results provide the basis for clinical resistance to BTK degraders and will inform therapy sequencing and the development of next-generation degrader therapies.

2026-05-08 | GSE330399 | GEO

NFKBIE-mutated CLL cells reshape the immune microenvironment and display selective resistance to BTK inhibitor treatment

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.

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BTK/PLCG2 mutations in CLL

Project description:Targeted sequencing in ibrutinib treated CLL

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Impact of the clinically approved BTK inhibitors on the conformation of full-length BTK and analysis of the development of BTK resistance mutations in chronic lymphocytic leukemia.

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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SpiD3-treated Human OSU-CLL cells LC-MSMS

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CITE-Seq profiling of CLL under ibrutinib treatment reveals transcriptional evolution of leukemic and immune cells.

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.

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Trascriptional profiling of proliferating and resting fracntions in ibrutinib-treated CLL

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