Ontology highlight
ABSTRACT:
PROVIDER: PRJNA838456 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Deterministic evolution and stringent selection during pre-neoplasia
| PRJNA951465 | ENA
Project description:Deterministic evolution and stringent selection during pre-neoplasia
| PRJNA951466 | ENA
Project description:It is elusive whether clonal selection of tumor cells in response to ionizing radiation (IR) is a deterministic or stochastic process. With high resolution clonal barcoding and tracking of over 400.000 HNSCC patient-derived tumor cells the clonal dynamics of tumor cells in response to IR was analysed. Fractionated IR induced a strong selective pressure for clonal reduction. This significantly exceeded uniform clonal survival probabilities indicative for a strong clone-to clone difference within tumor cells. Survival to IR is driven by a deterministic clonal selection of a smaller population which commonly survives radiation, while increased clonogenic capacity is a result of clonal competition of cells which have been selected stochastically. The ratio of these parameters is amenable to radiation sensitivity which correlates to prognostic biomarkers of HNSCC. Evidence for the existence of a rare subpopulation with an intrinsically radiation resistant phenotype was found at a frequency of 0.6-3.3%. With cellular barcoding we introduce a novel functional heterogeneity associated qualitative readout for evaluating the contribution of stochastic and deterministic clonal selection processes in response to IR.
2021-09-07 | E-MTAB-9693 | biostudies-arrayexpress
Project description:The B cell-specific BACH2 transcription factor is required for affinity maturation of mature B cells. Here, we show that Bach2 mediates negative selection at the pre-B cell receptor checkpoint and functions as a critical safeguard against leukemogenesis. Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments, and thus lack pre-B cell receptor expression. Upon productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends negative selection through BCL6-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, Bach2-mediated checkpoint control is frequently compromised and low levels of Bach2 expression represent a strong independent predictor of poor clinical outcome. Bach2+/+ pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53. Upon transformation with Myc, Bach2-/- pre-B cells fail to upregulate p53, form large colonies and initiate fatal leukemia in transplant recipient mice. ChIP-seq and gene expression analyses revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and multiple other checkpoint control genes. These findings identify Bach2 as a key activator of p53 in pre-B cells, which is critical to maintain stringency of the pre-B cell receptor checkpoint and an important barrier against leukemic transformation. ChIP-seq using BACH2 and BCL6 antibodies in OCI-Ly7 cells
2013-06-27 | E-GEOD-44420 | biostudies-arrayexpress
Project description:It is elusive whether clonal selection of tumor cells in response to ionizing radiation (IR) is a deterministic or stochastic process. With high resolution clonal barcoding and tracking of over 400.000 HNSCC patient-derived tumor cells the clonal dynamics of tumor cells in response to IR was analysed. Fractionated IR induced a strong selective pressure for clonal reduction. This significantly exceeded uniform clonal survival probabilities indicative for a strong clone-to clone difference. within tumor cells. Survival to IR is driven by a deterministic clonal selection of a smaller population which commonly survives radiation, while increased clonogenic capacity is a result of clonal competition of cells which have been selected stochastically. The ratio of these parameters is amenable to radiation sensitivity which correlates to prognostic biomarkers of HNSCC. Evidence for the existence of a rare subpopulation with an intrinsically radiation resistant phenotype was found at a frequency of 0.6-3.3%. With cellular barcoding we introduce a novel functional heterogeneity associated qualitative readout for evaluating the contribution of stochastic and deterministic clonal selection processes in response to IR. To analyze transcriptomic changes of HNSCC cell lines after fractionated Photon IR (5x4Gy), RNAseq analysis was performed on irradiated cells in comparison to untreated control cells (EBI submission E-MTAB-9693)
2021-08-31 | E-MTAB-10685 | biostudies-arrayexpress
Project description:The B cell-specific BACH2 transcription factor is required for affinity maturation of mature B cells. Here, we show that Bach2 mediates negative selection at the pre-B cell receptor checkpoint and functions as a critical safeguard against leukemogenesis. Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments, and thus lack pre-B cell receptor expression. Upon productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends negative selection through BCL6-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, Bach2-mediated checkpoint control is frequently compromised and low levels of Bach2 expression represent a strong independent predictor of poor clinical outcome. Bach2+/+ pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53. Upon transformation with Myc, Bach2-/- pre-B cells fail to upregulate p53, form large colonies and initiate fatal leukemia in transplant recipient mice. ChIP-seq and gene expression analyses revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and multiple other checkpoint control genes. These findings identify Bach2 as a key activator of p53 in pre-B cells, which is critical to maintain stringency of the pre-B cell receptor checkpoint and an important barrier against leukemic transformation.
2013-06-27 | GSE44420 | GEO
Project description:Based on inheritance of acquired characteristics, Lamarckian theory of evolution explains the evolution of biological systems through epigenetics. In a previous study, we have shown how microbial evolution has resulted in a persistent reduction in expression after repeatedly selecting for the lowest PGAL1-YFP-expressing cells. Applying the ATAC-seq assay on samples collected from this 28-days evolution experiment, here we show how genome-wide chromatin compaction change during evolution under selection pressure. We found that the chromatin compaction was altered not only on GAL network genes directly impacted by the selection pressure, showing an example of non-genetic memory, but also at the whole genome level. The GAL network genes experienced chromatin compaction accompanying the reduction in PGAL1-YFP reporter expression; strikingly, the fraction of global genes with differentially compacted chromatin states accounted for about a quarter of the total genome. Moreover, some of the ATAC-seq peaks followed well-defined temporal dynamics. Comparing the peak’s intensity in consecutive days, we found most of the differential compaction to occur between days 0 and 3 when the selection pressure was first applied, and between days 7 and 10 when the pressure was lifted. Among the gene sets enriched for the differential compaction events, some had increased chromatin availability once selection pressure was applied and decreased availability after the pressure was lifted (or vice versa). These results intriguingly show that, despite the lack of targeted selection, transcriptional availability of a large fraction of the genome change in a very diverse manner during evolution and these changes can occur in a relatively short number of generations.
2022-09-13 | GSE205227 | GEO
Project description:Protective immune responses to many pathogens depend on the development of high affinity antibody-producing plasma cells in germinal centers. Transgenic models suggest that there is a stringent affinity-based barrier to plasma cell development. Whether a similar high affinity barrier regulates plasma cell development under physiologic circumstances, and the nature of the plasma cell fate decision has not been defined precisely. Here we use a fate mapping approach to examine the relationship between germinal center (GC) B cells selected to undergo additional rounds of affinity maturation, germinal center pre-plasma cells and plasma cells. The data show that initial plasma cell selection overlaps with germinal center B cell selection, but that the plasma cell compartment accumulates a less diverse and higher affinity collection of antibodies over time. Thus, whereas the GC continues to diversify over time, affinity-based pre-plasma cell selection sieves the germinal center to enable accumulation of a more restricted group of high affinity antibody secreting plasma cells.
2023-11-02 | GSE246382 | GEO
Project description:Resistance towards cancer treatment represents a major clinical obstacle, preventing cure of cancer patients. To gain mechanistic insights, we developed a model for acquired resistance to chemotherapy by treating mice carrying patient derived xenografts (PDX) of acute lymphoblastic leukemia with widely-used cytotoxic drugs for 18 consecutive weeks. In two distinct PDX samples, tumors initially responded to treatment, until stable disease and eventually tumor re-growth evolved under therapy, at highly similar kinetics between replicate mice. Notably, replicate tumors developed different mutations in TP53 and individual sets of chromosomal alterations, suggesting independent parallel clonal evolution rather than selection, driven by a combination of stochastic and deterministic processes. Transcriptome and proteome showed shared dysregulations between replicate tumors providing putative targets to overcome resistance. In vivo CRISPR/Cas9 dropout screen in PDX revealed broad dependency on BCL2, BRIP1 and COPS2. Accordingly, venetoclax re-sensitized derivative tumors towards chemotherapy, despite genomic heterogeneity, demonstrating direct translatability of the approach. Hence, despite presence of multiple resistanceassociated genomic alterations, effective rescue treatment for polychemotherapyresistant tumors can be identified using functional testing in preclinical models.
2023-01-02 | PXD036517 | Pride