Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL

ABSTRACT: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially improved therapeutic options for chronic lymphocytic leukemia (CLL). Although ibrutinib is not curative, it has a profound effect on CLL cells and may create new pharmacologically exploitable vulnerabilities. To identify such vulnerabilities, we developed a systematic approach that combines epigenome profiling (charting the gene-regulatory basis of cell state) with single-cell chemosensitivity profiling (quantifying cell-type-specific drug response) and bioinformatic data integration. By applying our method to a cohort of matched patient samples collected before and during ibrutinib therapy, we identified characteristic ibrutinib-induced changes that provide a starting point for the rational design of ibrutinib combination therapies. Specifically, we observed and validated preferential sensitivity to proteasome, PLK1, and mTOR inhibitors during ibrutinib treatment. More generally, our study establishes a broadly applicable method for investigating treatment-specific vulnerabilities by integrating the complementary perspectives of epigenetic cell states and phenotypic drug responses in primary patient samples.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100672 | GEO | 2019/01/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Longitudinal omics data and preclinical treatment identify proteasome inhibition as therapy for ibrutinib-resistant CLL

Project description:Chronic lymphocytic leukemia (CLL) is a malignant lymphoproliferative disorder characterized by the accumulation of small mature B cells in blood and secondary lymphoid tissues. Novel drugs, such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, have greatly improved survival of CLL patients, nevertheless acquired drug resistance represents a major challenge the molecular mechanisms of which have not been fully elucidated yet. To overcome this limitation, we generated a mouse model of ibrutinib resistance by treating mice upon adoptive transfer of Eµ-TCL1 leukemia (TCL1-CLL) continuously with ibrutinib. After an initial response to the treatment, relapse under therapy occurs with an aggressive outgrowth of malignant cells, resembling observations in patients. To unravel relapse mechanism, we performed transcriptome and proteome analyses of sorted TCL1-CLL cells both during treatment and after relapse. Comparative analysis of these omics layers suggested alterations in the proteasome activity as a driver of ibrutinib resistance. Accordingly, we showed that preclinical treatment with the irreversible proteasome inhibitor (PI) carfilzomib administered upon ibrutinib resistance prolonged survival of mice, thus acting as salvage therapy. Longitudinal proteomic analysis of CLL patients with ibrutinib resistance identified deregulation in protein post-translational modifications. In addition, CLL cells from ibrutinib-resistant patients effectively responded to several PIs in co-culture assays. Altogether, our results from orthogonal omics approaches identified proteasome inhibition as potentially attractive salvage treatment option for CLL patients resistant or refractory to ibrutinib.

2024-12-10 | PXD053512 | Pride

Longitudinal omics data followed by preclinical treatment studies identify proteasome inhibition as potential salvage strategy for ibrutinib-resistant CLL

Project description:Chronic lymphocytic leukemia (CLL) is a malignant lymphoproliferative disorder characterized by the accumulation of small mature B cells in blood and secondary lymphoid tissues. Novel drugs, such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, have greatly improved survival expectations of CLL patients, nevertheless acquired drug resistance represents a major challenge the molecular mechanisms of which have not been elucidated yet. In order to fill this knowledge gap, we generated a mouse model of ibrutinib resistance by treating mice upon adoptive transfer of Eµ-TCL1 leukemia (TCL1-CLL) continuously with ibrutinib. After an initial response to the treatment, relapse under therapy occurs with an aggressive outgrowth of the malignant cells, resembling observations in patients. To unravel relapse mechanism, we performed transcriptome and proteome analyses of sorted TCL1-CLL cells both during treatment and after relapse. Comparative analysis of these omics layers suggested alterations in the proteasome activity as a driver of ibrutinib resistance. Accordingly, we showed that preclinical treatment with the irreversible proteasome inhibitor (PI) carfilzomib administered upon ibrutinib resistance prolonged survival of mice, thus acting as salvage therapy. Longitudinal proteomic analysis of CLL patients with ibrutinib resistance identified deregulation in protein post-translational modifications. In addition, CLL cells from ibrutinib-resistant patients effectively responded to several PIs in co-culture assays. Altogether, our results from orthogonal omics approaches identified proteasome inhibition as potentially attractive innovative salvage treatment option for CLL patients resistant or refractory to ibrutinib.

2024-12-10 | PXD037314 | Pride

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.

2020-12-15 | GSE152469 | GEO

Longitudinal omics data followed by preclinical treatment studies identify proteasome inhibition as potential salvage strategy for ibrutinib-resistant CLL

Project description:Chronic lymphocytic leukemia (CLL) is a malignant lymphoproliferative disorder characterized by the accumulation of small mature B cells in blood and secondary lymphoid tissues. Novel drugs, such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, have greatly improved survival expectations of CLL patients, nevertheless acquired drug resistance represents a major challenge and the complete molecular mechanisms of which have not been elucidated yet. In order to fill this knowledge gap, we generated a mouse model of ibrutinib resistance by treating mice upon adoptive transfer of Eµ-TCL1 leukemia (TCL1-CLL) continuously with ibrutinib. After an initial response to the treatment, relapse under therapy occurs with an aggressive outgrowth of the malignant cells, resembling observations in patients. To unravel relapse mechanism, we performed transcriptome and proteome analyses of sorted TCL1-CLL cells both during treatment and after relapse. Comparative analysis of these omics layers suggested alterations in the proteasome activity as a driver of ibrutinib resistance. Accordingly, we showed that preclinical treatment with the irreversible proteasome inhibitor (PI) carfilzomib administered upon ibrutinib resistance prolonged survival of mice, thus acting as salvage therapy. Longitudinal proteomic analysis of CLL patients with ibrutinib resistance identified deregulation in protein post-translational modifications. In addition, CLL cells from ibrutinib-resistant patients effectively responded to several PIs in co-culture assays. Altogether, our results from orthogonal omics approaches identified proteasome inhibition as potentially attractive innovative salvage treatment option for CLL patients resistant or refractory to ibrutinib.

2024-10-29 | GSE215414 | GEO

Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia

Project description:Chronic lymphocytic leukemia (CLL) is a genetically, epigenetically, and clinically heterogeneous disease. Despite this heterogeneity, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib provides effective treatment for the vast majority of CLL patients. To define the underlining regulatory program, we analyzed high-resolution time courses of ibrutinib treatment in closely monitored patients, combining cellular phenotyping (flow cytometry), single-cell transcriptome profiling (scRNA-seq), and chromatin mapping (ATAC-seq). We identified a consistent regulatory program shared across all patients, which was further validated by an independent CLL cohort. In CLL cells, this program starts with a sharp decrease of NF-κB binding, followed by reduced regulatory activity of lineage-defining transcription factors (including PAX5 and IRF4) and erosion of CLL cell identity, finally leading to the acquisition of a quiescence-like gene signature which was shared across several immune cell types. Nevertheless, we observed patient-to-patient variation in the speed of its execution, which we exploited to predict patient-specific dynamics in the response to ibrutinib based on pre-treatment samples. In aggregate, our study describes the cellular, molecular, and regulatory effects of therapeutic B cell receptor inhibition in CLL at high temporal resolution, and it establishes a broadly applicable method for epigenome/transcriptome-based treatment monitoring. This SuperSeries is composed of the SubSeries listed below.

2019-02-22 | GSE111015 | GEO

Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia [scRNA-seq]

2019-02-22 | GSE111014 | GEO

Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia [ATAC-seq]

2019-02-22 | GSE111013 | GEO

Multi-omics exploration of microenvironmental changes during BTK covalent inhibition in chronic lymphocytic leukemia

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

Targeting DNMT3A-mediated oxidative phosphorylation to overcome ibrutinib resistance in mantle cell lymphoma

Project description:The use of Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib has achieved a remarkable clinical response in mantle cell lymphoma (MCL). Acquired drug resistance, however, is significant and impacts long-term survival of MCL patients. Here we demonstrate that DNMT3A is involved in ibrutinib resistance. We found that DNMT3A expression is upregulated upon ibrutinib treatment in ibrutinib-resistant MCL cells. Genetic and pharmacological analyses revealed that DNMT3A mediates ibrutinib resistance independent of its DNA-methylation function. Mechanistically, DNMT3A induces the expression of MYC target genes through interaction with the transcription factors MEF2B and MYC, thus mediating metabolic reprogramming to oxidative phosphorylation (OXPHOS). Targeting DNMT3A by a low dose of decitabine inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting DNMT3A-medited metabolic reprogramming to OXPHOS with decitabine provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory MCL.

2024-02-19 | GSE227976 | GEO

Clonal Evolution in Patients with Chronic Lymphocytic Leukemia

Project description:<p>We analyzed clonal evolution in serial samples from five CLL patients who became resistant to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, using whole-exome and deep targeted sequencing. We observe a BTK-C481S mutation in one of five patients, and multiple PLCG2 mutations in a second patient. The other patients had an expansion of clones harboring del(8p) carrying additional driver mutations (EP300, MLL2, EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. We calculated the growth kinetics of ibrutinib-resistant subclones and estimated the size of the resistant clones at treatment initiation, which we validated by droplet-microfluidic technology. Haplo-insufficiency of TRAIL-R, a consequence of del(8p), led to TRAIL insensitivity which may contribute to development of ibrutinib resistance. These findings demonstrate that ibrutinib therapy has the potential to lead to clonal selection and expansion of rare cell populations already present at the time of treatment initiation. They also provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance, previously attributed solely to mutations in BTK and related pathway molecules.</p>

| phs001091 | dbGaP

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data