Evolution of advanced chronic lymphoid leukaemia unveiled by single-cell transcriptomics: a case study
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE150930 | GEO | 2020/10/27
REPOSITORIES: GEO
Similar Datasets
Project description:Evolution of advanced chronic lymphoid leukaemia unveiled by single-cell transcriptomics: a case study
| PRJNA634108 | ENA
Project description:Genetic and transcriptional heterogeneity of Chronic lymphocytic leukaemia (CLL) limits prevention of disease progression. Longitudinal single-cell transcriptomics represents the state-of-the-art method to profile the disease heterogeneity at diagnosis and to inform about disease evolution. Here, we apply single-cell RNA-seq to a CLL case, sampled at diagnosis and relapse, that was treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) and underwent a dramatic decrease in CD19 expression during disease progression. Computational analyses revealed a major switch in clones' dominance during treatment. The clone that expanded at relapse showed 17p and 3p chromosomal deletions, and up-regulation of pathways related to motility, cytokine signaling and antigen presentation. Single-cell RNA-seq uniquely revealed that this clone was already present at low frequency at diagnosis, and it displays feature of plasma cell differentiation, consistent with a more aggressive phenotype. This study shows the benefit of single-cell profiling of CLL heterogeneity at diagnosis, to identify clones that might otherwise not be recognized and to determine the best treatment options.
| S-EPMC7664833 | biostudies-literature
Project description:Longitudinally sampled peripheral blood samples of 9 CLL patients were subjected to single cell RNA sequencing before and at relapse after chemotherapy with fludarabine, cyclophosphamide and rituximab (FCR); allogeneic hematopoietic stem cell transplantation (RIC allo-HSCT); ibrutinib treatment, or before and after transformation to Richter's syndrome.
2021-06-09 | GSE165087 | GEO
Project description:We assessed genome-wide expression of available pretreatment specimens from CLL patients enrolled in REACH, a study of fludarabine and cyclophosphamide FC or R-FC (addition of rituximab to FC) in relapsed CLL, to understand the disease heterogeneity and explore genes that may be prognostic or predictive of benefit from R-FC treatment. REACH (NCT00090051) was registered at www.clinicaltrials.gov. This dataset supports the manuscript "PTK2 expression and immunochemotherapy outcome in chronic lymphocytic leukemia" by Weisser et al.
2014-07-30 | GSE58211 | GEO
Project description:We assessed genome-wide expression of available pretreatment specimens from CLL patients enrolled in REACH, a study of fludarabine and cyclophosphamide FC or R-FC (addition of rituximab to FC) in relapsed CLL, to understand the disease heterogeneity and explore genes that may be prognostic or predictive of benefit from R-FC treatment. REACH (NCT00090051) was registered at www.clinicaltrials.gov. This dataset supports the manuscript "PTK2 expression and immunochemotherapy outcome in chronic lymphocytic leukemia" by Weisser et al. 300 available pretreatment specimens from patients enrolled in REACH trial were analyzed. Additional contributers: REACH study investigators and patients
2014-07-30 | E-GEOD-58211 | biostudies-arrayexpress
Project description:Purpose: Accurate prediction of clinical response is the prerequisite for individualized therapy in chronic lymphocytic leukemia (CLL). We hypothesized that sequential assessment of gene expression changes early during therapy may well reflect behaviour of the leukemic clone in response to specific drugs. Patients and Methods: Gene expression profiles (GEP) were determined in CD19+ selected B-cells from 20 patients treated with fludarabine and cyclophosphamide (FC) (N=10) or FC plus rituximab (FCR) (N=10). Samples were collected in the first cycle before and within 48hours after initiation of treatment. GEP analysis was stratified by clinical response 3 months after start of therapy. Results: GEP before treatment detected high expression of 34 genes correlated with response and 32 genes correlated with resistance to therapy. These genes were related to regulation of apoptosis, cell cycle, cell adhesion, and signal transduction. Different results were obtained with sequential GEP: Sixteen genes were up-regulated after rituximab infusion in non-responders. Rituximab therapy resulted in down-regulation of AKT1 indicating involvement of the PI3-kinase pathway in CD20-signaling. Up-regulation of 24 genes after FC (including ITPKB (inositol 1,4,5-trisphosphate 3-kinase) and CD44) and of 36 genes after FCR (including CD49d) was associated with resistance. Down-regulation of CTLA4 correlated with poor response to FC. CD44, CD49d and the PI3-kinase signaling pathway were confirmed as potential therapeutic targets to overcome resistance by (protein analysis) or functional experiments. Conclusion Sequential GEP provides rapid and relevant information for prediction of response and resistance. This approach could be used to guide and adapt individualized therapy in CLL. 50 Samples from CD19 selected B-cells, three treatments (rituximab, FC and RFC), 10 replicates for each treatment, 20 replicates for control condition
2011-03-01 | E-GEOD-15490 | biostudies-arrayexpress
Project description:To define clonal evolution of somatic copy number alterations (CNAs) in chronic lymphocytic leukemia (CLL), sequential samples of 103 individuals were investigated by SNP-array analysis for appearance of novel CNAs. Patients were enrolled on the CLL8 trial and uniformly received fludarabine, cyclophosphamide +/- rituximab (FC/FCR). Comparing two sequential samples prior to therapy (N=27, a median of 2.9 years apart), CNA evolution occurred in 19% of cases. In contrast, when comparing treatment‑initiation and relapse genomic profiles (a median of 3.6 years apart), CNA evolution was seen in 40% of cases. This suggested association of FC(R) treatment with higher rate of CNA evolution. The only clinical feature significantly associated with CNA evolution was FCR therapy compared with FC (OR=2.806, p=0.024). As this might be related to narrower evolutionary bottlenecks imposed by the more effective FCR therapy, which could execute more selection pressure, we examined matched minimal residual disease data. We found CNA evolution more frequently in cases with CLL cell numbers rapidly receding in early phases of treatment. Finally, we observed frequent rises of TP53 mutant/deficient clones with therapy (N=19, 22%) that were associated with decreased overall survival (p=0.016). These results demonstrated that re-examination of TP53 status upon relapse provides important information.
2017-08-25 | GSE83566 | GEO
Project description:Chromosomal aberrations are a hallmark of acute lymphoid leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed genome-wide analysis of leukaemic blasts from 242 paediatric ALL patients using high-resolution single nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding key regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL. PAX5 was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in haploinsufficiency or the generation of hypomorphic alleles. Deletions were also detected in E2A, EBF, LEF1, Ikaros, and Aiolos. These findings demonstrate that direct disruption of pathways controlling B cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify critical new molecular lesions in cancer. Keywords: disease state analysis *** Due to privacy concerns, the primary SNP array data is no longer available with unrestricted access. Individuals wishing to obtain this data for research purposes may request access using the Web links below. ***
2009-09-02 | GSE5511 | 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:Purpose: Accurate prediction of clinical response is the prerequisite for individualized therapy in chronic lymphocytic leukemia (CLL). We hypothesized that sequential assessment of gene expression changes early during therapy may well reflect behaviour of the leukemic clone in response to specific drugs. Patients and Methods: Gene expression profiles (GEP) were determined in CD19+ selected B-cells from 20 patients treated with fludarabine and cyclophosphamide (FC) (N=10) or FC plus rituximab (FCR) (N=10). Samples were collected in the first cycle before and within 48hours after initiation of treatment. GEP analysis was stratified by clinical response 3 months after start of therapy. Results: GEP before treatment detected high expression of 34 genes correlated with response and 32 genes correlated with resistance to therapy. These genes were related to regulation of apoptosis, cell cycle, cell adhesion, and signal transduction. Different results were obtained with sequential GEP: Sixteen genes were up-regulated after rituximab infusion in non-responders. Rituximab therapy resulted in down-regulation of AKT1 indicating involvement of the PI3-kinase pathway in CD20-signaling. Up-regulation of 24 genes after FC (including ITPKB (inositol 1,4,5-trisphosphate 3-kinase) and CD44) and of 36 genes after FCR (including CD49d) was associated with resistance. Down-regulation of CTLA4 correlated with poor response to FC. CD44, CD49d and the PI3-kinase signaling pathway were confirmed as potential therapeutic targets to overcome resistance by (protein analysis) or functional experiments. Conclusion Sequential GEP provides rapid and relevant information for prediction of response and resistance. This approach could be used to guide and adapt individualized therapy in CLL.
2011-03-01 | GSE15490 | GEO