Ontology highlight
ABSTRACT:
PROVIDER: PRJNA381632 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5413650_1.fastq.gz | Fastqsanger.gz | |||
| SRR5413650_2.fastq.gz | Fastqsanger.gz | |||
| SRR5413660_1.fastq.gz | Fastqsanger.gz | |||
| SRR5413660_2.fastq.gz | Fastqsanger.gz | |||
| SRR5413670_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 64 |
Similar Datasets
Project description:Clonal and subclonal evolution is involved in the progression of chronic lymphocytic leukemia (CLL). Evolution can work to select not only genetic mutations, but also epigenetic states. Here we performed a long-term longitudinal DNA methylation profiling study of CLL patients to look for associations of epigenetic evolution to different disease courses. In line with the genetic data, large-scale methylation evolution was not present in any of the evaluated long-term untreated (n = 3) and relapsed (n = 2) patients displaying clonal changes of linear type while 3 of the 5 examined refractory patients featured profound changes in DNA methylation.
2021-03-15 | GSE143411 | GEO
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:Richter syndrome (RS) occurs in up to 15% of patients with chronic lymphocytic leukemia (CLL). While RS, usually represented by the histologic transformation to a diffuse large B-cell lymphoma (DLBCL), is associated with a very poor outcome, especially when clonally related to the pre-existing CLL, mechanisms leading to RS have not been clarified yet. To better understand the pathogenesis of RS, we analyzed a series of cases including: 59 RS, 28 CLL-phase of RS, 315 CLL and 127 de novo DLBCL. RS demonstrated a genomic complexity intermediate between CLL and DLBCL. Cell cycle deregulation via inactivation of TP53 and of CDKN2A was a main mechanism in the histologic transformation from CLL-phase, being present in approximately half of the cases, and affected the outcome of the RS patients. A second major subgroup was characterized by the presence of trisomy 12 and comprised one third of the cases. While RS shared some of the lesions seen in de novo DLBCL, its genomic profile was clearly separate. The CLL-phase preceding RS had not a generalized increase in genomic complexity when compared with untransformed CLL, but it presented clear differences in the frequency of specific genetic lesions. Genomic profiling of Richter-syndrome Chronic Lymphocytic Leukemia
2013-09-20 | E-GEOD-50252 | biostudies-arrayexpress
Project description:Genetic and epigenetic intra-tumoral heterogeneity cooperate to shape the evolutionary course of cancer. In addition to genetic mutations, chronic lymphocytic leukemia (CLL) undergoes diversification through stochastic DNA methylation changes – epimutations. To measure the epimutation rate at single-cell resolution, we applied multiplexed reduced representation bisulfite sequencing (MscRRBS) to healthy donors B cells and CLL patient samples. We observed that the common clonal CLL origin results in consistently elevated epimutation rate (i.e., low cell-to-cell epimutation rate variability). In contrast, variable epimutation rates across normal B cells reflect diverse evolutionary ages across the B cell differentiation trajectory, consistent with epimutations serving as a molecular clock. Heritable epimutation information allowed high-resolution lineage reconstruction with single-cell data, applicable directly to patient sample. CLL lineage tree shape revealed earlier branching and longer branch lengths than normal B cells, reflecting rapid drift after the initial malignant transformation and a greater proliferative history. To validate the inferred tree topology, we integrated MscRRBS with single-cell transcriptomes and genotyping, which confirmed that genetic subclones map to distinct clades inferred solely based on epimutation information. Lastly, to examine potential lineage biases during therapy, we profiled serial CLL samples prior to and during ibrutinib-associated lymphocytosis. Lineage trees revealed divergent clades of cells preferentially expelled from the lymph node with ibrutinib therapy, marked by distinct transcriptional profiles. These data offer direct single-cell integration of genetic, epigenetic and transcriptional information in the study of leukemia evolution, providing deeper insight into its lineage topology and enabling the charting of its evolution with therapy.
2019-05-02 | GSE109085 | GEO
Project description:Clonal evolution in CLL patients treated with ibrutinib
| PRJEB32120 | ENA
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.
2024-04-02 | GSE249956 | GEO
Project description:<p><b>Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation</b></p> <p>The pathogenesis of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is still largely unknown since the full spectrum of genetic lesions that are present in the CLL genome, and therefore the number and identity of dysregulated cellular pathways, have not been identified. By combining next-generation sequencing and copy number analysis, we show here that the typical CLL coding genome contains less than 20 clonally represented gene alterations/case, including predominantly non-silent mutations and fewer copy number aberrations. These analyses led to the discovery of several genes not previously known to be altered in CLL. While most of these genes were affected at low frequency in an expanded CLL screening cohort, mutational activation of NOTCH1, observed in 8.3% of CLL at diagnosis, was detected at significantly higher frequency during disease progression toward Richter transformation (31.0%) as well as in chemorefractory CLL (20.8%). Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the disease, NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival. These results provide initial data on the complexity of the CLL coding genome and identify a dysregulated pathway of diagnostic and therapeutic relevance.</p> <p><b>Genetic Lesions associated with Chronic Lymphocytic Leukemia transformation to Richter Syndrome</b></p> <p>Richter syndrome (RS) derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B cell type (DLBCL). The molecular pathogenesis of RS is only partially understood. By combining whole-exome sequencing and copy-number analysis of 9 CLL-RS pairs and of an extended panel of 43 RS cases, we show that this aggressive disease typically arises from the predominant CLL clone by acquiring an average of ~20 genetic lesions/case. RS lesions are heterogeneous in terms of load and spectrum among patients, and include those involved in CLL progression and chemorefractoriness (TP53 disruption and NOTCH1 activation) as well as some not previously implicated in CLL or RS pathogenesis. In particular, disruption of the CDKN2A/B cell cycle regulator locus is associated with ~30% of RS cases. Finally, we report that the genomic landscape of RS is significantly different from that of de novo DLBCL, suggesting that they represent distinct disease entities. These results provide insights into RS pathogenesis, and identify dysregulated pathways of potential diagnostic and therapeutic relevance.</p>
| phs000364 | dbGaP
Project description:Single-agent anti-PD-1 antibodies lack clinical efficacy in patients with chronic lymphocytic leukemia (CLL). Here, we study the peripheral blood samples from high-risk or relapsed/refractory CLL before and after combination therapy of ibrutinib, fludarabine, and pembrolizumab (IFP). We performed bulk RNA-sequencing (bulk RNA-seq) to detect the transcriptomic changes of CLL and T cells during treatment, and demonstrated the immune responses of CD8 T cells to pembrolizumab by single-cell RNA sequencing (scRNA-Seq).
2025-08-27 | GSE283397 | GEO
Project description:To identify genomic alterations contributing to the pathogenesis of high‑risk chronic lymphocytic leukemia (CLL) beyond the well‑established role of TP53 aberrations, we comprehensively analyzed 146 high‑risk CLL cases by single‑nucleotide polymorphism (SNP)‑arrays and targeted next‑generation sequencing including 75 relapsed/refractory and 71 treatment‑naïve high‑risk cases from prospective clinical trials. Increased genomic complexity was a hallmark of relapsed/refractory and treatment‑naïve high‑risk CLL, and was associated with TP53 and ATM dysfunction. In relapsed/refractory cases previously exposed to the selective pressure of chemo(immuno)therapy, gain(8)(q24.21) and del(9)(p21.3) were found particularly enriched. Both of these copy number alterations (CNAs) affected key regulators of cell cycle progression, namely c‑MYC and CDKN2A/B. Gains in 8q24.21 were either focal gains in a c‑MYC enhancer region or larger gains directly affecting the c‑MYC locus, but only the latter type was highly enriched in relapsed/refractory CLL (17%). Loss of CDKN2A/B was found frequently to co‑occur with gain of c‑MYC and in this combination it was likely associated with Richter transformation. In addition to a high frequency of NOTCH1 mutations (23%), we found recurrent genetic alterations in SPEN (4% mutated), RBPJ (8% deleted) and SNW1 (8% deleted), all affecting a protein complex that represses transcription of NOTCH1 target genes. We investigated the functional impact of these alterations on HES1, DTX1 and c‑MYC gene transcription and found de‑repression of these NOTCH1 target genes particularly with SPEN mutations. In summary, we provide new insights into the pathogenesis of high‑risk CLL by defining novel recurrent CNAs and identifying alterations that likely contribute to disease refractoriness.
2020-05-06 | GSE131114 | GEO
Project description:Ibrutinib (Ibr), an orally administered covalent inhibitor of Bruton’s kinase, has generated remarkable responses in CLL patients including those with an unfavorable cytogenetic profile. Once patients develop resistance to ibrutinib, the outcome is poor with few treatment options. To further understand the genomic mechanisms underlying Ibr resistance, we’ve performed genome wide copy number analysis of serial samples collected from nine ibrutinib-relapsed patients. Deletions of 18p often coincide with del(17p)/TP53 mutations, predispose patients to relapse.
2017-04-06 | GSE97436 | GEO