Mapping the Cellular Origin and Early Evolution of Leukemia in Down Syndrome
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ABSTRACT:
PROVIDER: PRJNA671821 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Mapping the Cellular Origin and Early Evolution of Down Syndrome Leukemogenesis [miRNA-Seq]
| PRJNA671827 | ENA
Project description:Mapping the Cellular Origin and Early Evolution of Down Syndrome Leukemogenesis [CUT&RUN]
| PRJNA671815 | ENA
Project description:Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia. As Down syndrome leukemogenesis initiates during fetal development, we sought to characterize the cellular mechanisms of preleukemic initiation and leukemic progression using CRISPR/Cas9-mediated gene editing in human disomic and trisomic fetal liver hematopoietic cells and xenotransplantation. Compared to disomic fetal liver, trisomy 21 initiated atypical fetal hematopoiesis, in part through up-regulation of chromosome 21 miRNAs. GATA1 mutations caused transient preleukemia only when introduced into trisomy 21 long-term hematopoietic stem cells. By contrast, progression to leukemia was independent of trisomy 21 and originated in a wide spectrum of stem and progenitor cells through additional mutations in cohesin genes such as STAG2. CD117+ cells mediated the propagation and progression of the preleukemic and leukemic disease. Treatment with small molecule CD117/KIT inhibitors efficiently targeted preleukemic stem cells and blocked progression to leukemia; thereby laying the groundwork for early prevention strategies in Down syndrome newborns.
2021-07-08 | GSE160095 | GEO
Project description:Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia. As Down syndrome leukemogenesis initiates during fetal development, we sought to characterize the cellular mechanisms of preleukemic initiation and leukemic progression using CRISPR/Cas9-mediated gene editing in human disomic and trisomic fetal liver hematopoietic cells and xenotransplantation. Compared to disomic fetal liver, trisomy 21 initiated atypical fetal hematopoiesis, in part through up-regulation of chromosome 21 miRNAs. GATA1 mutations caused transient preleukemia only when introduced into trisomy 21 long-term hematopoietic stem cells. By contrast, progression to leukemia was independent of trisomy 21 and originated in a wide spectrum of stem and progenitor cells through additional mutations in cohesin genes such as STAG2. CD117+ cells mediated the propagation and progression of the preleukemic and leukemic disease. Treatment with small molecule CD117/KIT inhibitors efficiently targeted preleukemic stem cells and blocked progression to leukemia; thereby laying the groundwork for early prevention strategies in Down syndrome newborns.
2021-07-08 | GSE160093 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-07-08 | GSE160096 | GEO
Project description:Finding cellular origin of mouse kidney organoids
| PRJEB17924 | ENA
Project description:To investigate the mechanism by which GATA1s and STAG2 deficiency contribute to Down Syndrome leukemogenesis, specifically within the propagating CD34/CD117 cell fractions from primary xenografts, we carried out transcriptional and epigenetic profiling by RNAseq and ATACseq. The chromatin accessibility landscape was compared to bulk ATACseq of
individually sorted N-FL HSPC subpopulations.
To investigate the mechanism underlying the synergy between T21 and GATA1s in driving preleukemia development, we analyzed the binding occupancy of GATA1. We performed Cut&Run assays to profile
genome-wide GATA1 binding sites and also to quantify binding changes upon GATA1s editing in N-FL and T21-FL CD34+ enriched HSPCs. Lastly, we profiled miRNAs from N-FL and T21-FL CD34+ enriched
HSPCs by miRNA-Seq.
| EGAS00001004780 | EGA
Project description:Dedifferentiated liposarcoma (DDLPS) is the most frequent high-grade soft tissue sarcoma subtype. It is characterized by a component of undifferentiated tumor cells coexisting with a component of well-differentiated adipocytic tumor cells. Both dedifferentiated (DD) and well-differentiated (WD) components exhibit MDM2 amplification, however their cellular origin remains elusive. Using single-cell RNA sequencing and functional assays in paired WD and DD components from primary DDLPS tumors, we characterized the cellular heterogeneity of DDLPS tumor and micro-environment. We identified a population of tumor adipocyte stem cells (ASC) showing striking similarities with adipocyte stromal progenitors found in white adipose tissue. We show that tumor ASC harbor the ancestral genomic alterations of WD and DD components, suggesting that both derive from these progenitors following clonal evolution. Last, we show that DD tumor cells keep important biological properties of ASC including pluripotency and that their adipogenic properties are inhibited by a TGF-β high immunosuppressive tumor micro-environment.
2024-07-22 | GSE221492 | GEO
Project description:Dedifferentiated liposarcoma (DDLPS) is the most frequent high-grade soft tissue sarcoma subtype. It is characterized by a component of undifferentiated tumor cells coexisting with a component of well-differentiated adipocytic tumor cells. Both dedifferentiated (DD) and well-differentiated (WD) components exhibit MDM2 amplification, however their cellular origin remains elusive. Using single-cell RNA sequencing and functional assays in paired WD and DD components from primary DDLPS tumors, we characterized the cellular heterogeneity of DDLPS tumor and micro-environment. We identified a population of tumor adipocyte stem cells (ASC) showing striking similarities with adipocyte stromal progenitors found in white adipose tissue. We show that tumor ASC harbor the ancestral genomic alterations of WD and DD components, suggesting that both derive from these progenitors following clonal evolution. Last, we show that DD tumor cells keep important biological properties of ASC including pluripotency and that their adipogenic properties are inhibited by a TGF-β high immunosuppressive tumor micro-environment.
2024-07-22 | GSE221493 | GEO
Project description:The cellular origin of chronic lymphocytic leukemia (CLL) is debated. Transcriptome analysis of CLL and normal peripheral blood and splenic B cell subsets displayed highest similarity of CLL to mature CD5+ B cells. We identified a distinct CD5+CD27+ post-germinal center B cell subset, and revealed that immunoglobulin V gene mutated CLL are more similar to mutated CD5+ B cells, whereas unmutated CLL are more related to unmutated CD5+ B cells. Stereotyped immunoglobulin V gene rearrangements were significantly enriched among CD5+ B cells, providing further genetic evidence for a derivation of CLL from CD5+ B cells. Moreover, we identified deregulated expression patterns providing novel insights into the pathophysiology of CLL, including downregulation of EBF1 and KLF family members. Transcriptome profiling of CLL and healthy human blood and splenic mature B cell subsets. Identification of deregulated transcription patterns with implications on CLL pathobiology. Human mature B cell subsets and CLL with mutated (mCLL) and unmutated V gene status (uCLL) were purified from peripheral blood and spleen. Samples of 5 to 7 donors each were collected and processed in three batches in a two rounded in vitro transcription protocol. Retrieved data were batch corrected and subjected to analysis. Human mature CD5+ B cell subsets and CLL with mutated (mCLL) and unmutated V gene status (uCLL) were purified from peripheral blood.
2012-09-27 | E-GEOD-36907 | biostudies-arrayexpress