Ontology highlight
ABSTRACT:
PROVIDER: PRJNA552792 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9645460_1.fastq.gz | Fastqsanger.gz | |||
| SRR9645460_2.fastq.gz | Fastqsanger.gz | |||
| SRR9645470_1.fastq.gz | Fastqsanger.gz | |||
| SRR9645470_2.fastq.gz | Fastqsanger.gz | |||
| SRR9645480_1.fastq.gz | Fastqsanger.gz |
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Project description:B cell chronic lymphocytic leukemia - A model with immune response
Seema Nanda 1, , Lisette dePillis 2, and Ami Radunskaya 3,
1.
Tata Institute of Fundamental Research, Centre for Applicable Mathematics, Bangalore 560065, India
2.
Department of Mathematics, Harvey Mudd College, Claremont, CA 91711
3.
Department of Mathematics, Pomona College, Claremont, CA, 91711, United States
Abstract
B cell chronic lymphocytic leukemia (B-CLL) is known to have substantial clinical heterogeneity. There is no cure, but treatments allow for disease management. However, the wide range of clinical courses experienced by B-CLL patients makes prognosis and hence treatment a significant challenge. In an attempt to study disease progression across different patients via a unified yet flexible approach, we present a mathematical model of B-CLL with immune response, that can capture both rapid and slow disease progression. This model includes four different cell populations in the peripheral blood of humans: B-CLL cells, NK cells, cytotoxic T cells and helper T cells. We analyze existing data in the medical literature, determine ranges of values for parameters of the model, and compare our model outcomes to clinical patient data. The goal of this work is to provide a tool that may shed light on factors affecting the course of disease progression in patients. This modeling tool can serve as a foundation upon which future treatments can be based.
Keywords: NK cell, chronic lymphocytic leukemia, mathematical model, T cell., B-CLL.
2020-01-09 | MODEL2001090002 | BioModels
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:Mitochondrial mutations have the potential to act as natural barcodes that allow the tracking of heterogenous cell populations at the single cell level, but thus far, the dynamics of mitochondrial mutations across time and tissue compartments have not been extensively studied. This dataset was generated using mtscATAC-seq to track mitochondrial mutations in peripheral blood, bone marrow and lymph node from 9 patients with chronic lymphocytic leukemia (CLL) across different clinical scenarios. Our in-depth analysis reveals different patterns of dynamisms in mitochondrial mutations in patients undergoing watchful waiting, chemotherapy with fludarabine, cyclophosphamide and rituximab (FCR), allogeneic stem cell transplantation, ibrutinib treatment or transformation to Richter’s syndrome. We provide evidence that mitochondrial mutations can link CLL subclones with distinct chromatin cell states. Mitochondrial mutations appear to recapitulate disease history in CLL, providing patient-level support of the concept of in vivo natural barcodes as a means for understanding clonal dynamics in cancer.
2021-06-09 | GSE163579 | GEO
Project description:Here we measured genome-wide DNA methylation in patients with chronic lymphocytic leukemia as it provides an opportunity to capture the emergence of altered methylation landscapes as well as track their dynamics over disease progression including after treatment. Specifically, our cohort includes 21 CLL cases with up to six different time points, 20 precursor states of monoclonal B cell lymphocytes (MBL) and 5 matched samples from MBL and CLL states of the same patients. We find that across all CLL cases, a highly aberrant methylation state was present consistently already at the first time point and maintained with remarkable stability over disease progression. To improve our resolution and address heterogeneity we sequenced the methylome of single cells from CD5 positive and negative naïve and memory B cells as well as unsorted B cells and CLL cells. Methylation levels were highly similar within groups pointing to a rather homogeneous population and contrasted by pronounced differences between naïve and memory B cells that do not distinguish CD5 positive and negative subgroups. Our 20 patients with MBL further confirmed the early emergence of this landscape and surprisingly, the chemotherapy did not have a notable impact on the altered methylome despite a strong depletion of white blood cells.
2021-02-23 | GSE125499 | GEO
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
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.
2019-02-22 | GSE111013 | GEO
Project description:The identification of gene mutation and structural genomic aberrations that are critically involved in CLL pathogenesis is still evolving. One may postulate that genomic driver lesions with effects on CLL proliferation, apoptosis thresholds, or chemotherapy resistance should increase in frequency over time when measured sequentially in a large CLL cohort. We sequentially sampled a large, well-characterized CLL cohort at a mean of 4 years between samplings. The paired analysis included 156 patients, of whom 114 remained untreated and 42 received intercurrent therapies. Results: we identify a strong effect of intercurrent therapies on the frequency of acquisition of aCNAs in CLL. Importantly, the spectrum of acquired genomic changes was largely similar in patients that did or did not receive intercurrent therapies; therefore, various genomic changes that become part of the dominant clones are often already present in CLL cell populations prior to therapy. Further, we provide evidence that therapy of CLL with preexisting TP53 mutations results in the outgrowth of genomically very complex clones which dominate at relapse. Using complementary technologies directed at the detection of genomic events that are present in substantial proportions of of the clinically relevant CLL disease bulk, we capture aspects of genomic evolution in CLL over time, including increases in the frequency of genomic complexity, specific recurrent aCNAs, and TP53 mutations.
2013-04-19 | GSE45565 | GEO
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:The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous. Several prognostic factors have been identified that can stratify patients into groups that differ in their relative tendency for disease progression and/or survival. Here, we pursued a subnetwork-based analysis of gene expression profiles to discriminate between groups of patients with disparate risks for CLL progression. From an initial cohort of 130 patients, we identified 38 prognostic subnetworks that could predict the relative risk for disease progression requiring therapy from the time of sample collection, more accurately than established markers. The prognostic power of these subnetworks then was validated on two other cohorts of patients. We noted reduced divergence in gene expression between leukemia cells of CLL patients classified at diagnosis with aggressive versus indolent disease over time. The predictive subnetworks vary in levels of expression over time but exhibit increased similarity at later timepoints prior to therapy, suggesting that degenerate pathways apparently converge into common pathways that are associated with disease progression. As such, these results have implications for understanding cancer evolution and for the development of novel treatment strategies for patients with CLL. Leukemia cells were isolated from blood samples of CLL patients enrolled in the MILE study who had not received prior therapy for CLL, as per the MILE protocol22. Expression data were gathered from samples found to have a CLL cell population with greater than 90% CD5+CD19+, as accessed via flow cytometry. Total RNA was isolated and hybridized to Affymetrix HG-U133+2 GeneChips. This study is about the time to treatment, ie., prognosis instead of diagnosis.
2012-07-25 | E-GEOD-39671 | biostudies-arrayexpress