ScRNAseq of longitidunally acquired samples from a CLL patient
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE186150 | GEO | 2021/10/22
REPOSITORIES: GEO
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Project description:scRNAseq of longitidunally acquired samples from a CLL patient
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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:Many functional consequences of mutations on tumor phenotypes in chronic lymphocytic leukemia (CLL) are only partially known. This is in part due to a scarcity of information on the proteome of CLL. We profiled the proteome of 117 CLL samples with data-independent acquisition mass spectrometry (DIA-MS) and integrated the results with genomic, transcriptomic, functional data and clinical outcome. We found trisomy 12 and IGHV to be major determinants of proteome variation in CLL (1055 and 542 differential proteins FDR of 5%). Trisomy 12 was associated with limited protein abundance buffering. Protein complex analyses detected functional units involved in BCR/PI3K/AKT signaling in CLL with trisomy 12. We associated protein expression with response to anticancer drugs, and STAT2 protein expression emerged as a biomarker for the prediction of response to kinase inhibitors including BTK and MEK inhibitors. STAT2 protein levels were determined by gene dosage (trisomy 12), stabilization in a protein complex and linked to interferon signaling in CLL. This study highlights the emerging importance of protein abundance profiling in CLL biology.
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Project description:Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib represent an effective strategy for treatment of chronic lymphocytic leukemia (CLL), although ~30% of patients eventually undergo disease progression. Here we investigated the long-term modulation of the CXCR4dim/CD5bright proliferative fraction (PF) and the CXCR4bright/CD5dim resting fraction (RF) in CLL samples, and their correlation with therapeutic outcome and emergence of ibrutinib resistance. Longitudinal tracking by flow cytometry revealed that PF, initially suppressed by ibrutinib, reappeared upon early disease progression suggesting that PF evaluation could represent a sensitive and specific marker of CLL progression upon ibrutinib treatment. Transcriptomic analyses of PF at progression revealed similar proliferation signatures between pre- and post-treatment PF, demonstrating the emergence upon progression of a newly proliferating cell population.
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Project description:Microarray-based gene expression analysis identified genes differentially expressed in 6 MCL and 18 CLL patient samples compared in independent analyses to CD19 selected healthy donor B-cell samples.
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Project description: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.
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Project description:RNA sequencting of CLL cells treated by BTK degrader
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Project description:Deletion of the short arm of chromosome 17 (17p-) is one of the most critical genetic variants used in B-CLL risk stratification. The tumor suppressor TP53 maps to this region, and its loss or mutation significantly accelerates B-CLL progression, hampers response to chemotherapy, and shortens survival. While florescent in situ hybridization (FISH) analyses for 17p deletions are routinely performed during clinical diagnoses, mutational analyses of the TP53 gene is not widely available and thus its mutational status is often unknown in patients with CLL. Given the limited clinical data that exists for frontline treatment of patients with CLL harboring TP53 mutations, there is a great need to identify novel treatment strategies for this subset of patients. Herein, we use a CLL mouse model (Eμ-TCL1) in the presence or absence of a common TP53 hot-spot mutation (p53R172H, corresponding to p53R175H in humans) to study its impact on disease progression, survival, response to therapy, and dynamic loss of the remaining wild-type Trp53 allele during the course of B-CLL following BTK inhibitor (ibrutinib). We show that ibrutinib was effective in increasing survival and activated gene and cellular programs outside of the p53 pathway in both settings, and thus, did not place selective pressure on the remaining wild type Trp53 allele. These data demonstrate the potent effect of BTK-inhibition in B-CLL and more importantly, provide evidence that ibrutinib acts as an effective treatment for aggressive forms of B-CLL with TP53 mutation and potentially chemo-resistant refractory disease.
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