Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cell-Cycle Restriction Sustains Therapy-Resistant Pre-Leukemic Stem Cells

ABSTRACT: Pre-leukemic stem cells (pre-LSCs) provide a reservoir of cells that evolve to acute leukemia and cause relapse following chemotherapy. We postulated that quiescence of pre-LSCs is an important mechanism of therapeutic resistance. Using a doxycycline-inducible H2B-GFP transgene in a mouse model of T-cell acute lymphoblastic leukemia, we show that long-term self-renewal, clonal evolution and resistance to chemo-radiation are intrinsically linked to restricted cell cycle. We show that restricted cell cycle of pre-LSCs requires the presence of the CDK inhibitor p21, with absence of p21 leading to chemosensitivity and clonal extinction by loss of asymmetric cell division and terminal differentiation. These results provide a model to identify and test strategies to eradicate an important source of clonal evolution and leukemic relapse.

ORGANISM(S): Mus musculus

PROVIDER: GSE110132 | GEO | 2018/12/21

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Convergent Epigenetic Evolution Drives Relapse in Acute Myeloid Leukemia

Project description:Relapse of acute myeloid leukemia (AML) is highly aggressive and often treatment refractory. We analyzed previously published AML relapse cohorts and found that 40% of relapses occur without changes in driver mutations, suggesting that non-genetic mechanisms drive relapse in a large proportion of cases. We therefore characterized epigenetic patterns of AML relapse using 26 matched diagnosis-relapse samples with ATAC-seq. This analysis identified a relapse-specific chromatin accessibility signature for mutationally stable AML, suggesting that AML undergoes epigenetic evolution at relapse independent of mutational changes. Analysis of leukemia stem cell (LSC) chromatin changes at relapse indicated that this leukemic compartment underwent significantly less epigenetic evolution than non-LSCs, while epigenetic changes in non-LSCs reflected overall evolution of the bulk leukemia. Finally, we used single-cell ATAC-seq paired with mitochondrial sequencing (mtscATAC) to map clones from diagnosis into relapse along with their epigenetic features. We found that distinct mitochondrially-defined clones exhibit more similar chromatin accessibility at relapse relative to diagnosis, demonstrating convergent epigenetic evolution in relapsed AML. These results demonstrate that epigenetic evolution is a feature of relapsed AML and that convergent epigenetic evolution can occur following treatment with induction chemotherapy.

2024-04-17 | GSE256495 | GEO

Proteomics analysis for RBM17 in acute myeloid leukemia

Project description:Acute myeloid leukemia (AML) patients suffer from chemo-resistance, high relapse frequency, and low overall survival rate, outcomes driven by leukemic stem cells (LSCs). Understanding the molecular mechanisms that support these primitive leukemic cells is crucial for developing effective AML therapeutics. In the present study, we demonstrate that upregulation of the splicing factor RBM17 preferentially marks and sustains the primitive compartment of AML. We performed shotgun proteomics to characterize the proteome changes upon RBM17 knockdown in AMl cells. In addition, we used proteomics to analyze the proteome changes after knockdown of EIF4A2, a direct splicing substrate of RBM17 in AML cells.

2022-08-12 | PXD026780 | Pride

Cell quiescence and reprogramming are distinctive features of pre-leukemic stem cells [ATAC-seq]

Project description:The leukemic stem cell concept is well established in B-acute lymphoblastic leukemia (B-ALL). However, the question of how a primary oncogene reprograms stem cell-like properties in committed B-cells and leads to a pre-neoplastic population remains unclear. Here, we used the PAX5-ELN oncogenic model to demonstrate a causal link between the differentiation blockade, the self-renewal and the emergence of pre-leukemic stem cells (pre-LSCs). Through multi-parametric immunophenotyping, we show that PAX5-ELN oncoprotein disrupts the differentiation of pre-leukemic cells by enforcing the IL7r/JAK-STAT signaling pathway. This disruption is associated with the induction of rare and quiescent pre-LSCs that sustain the leukemia-initiating activity, as assessed using the H2B-GFP model. Integration of transcriptomic and chromatin accessibility data reveals that those quiescent pre-LSCs lose B-cell identity and reactivate an immature molecular program, reminiscent of human B-ALL chemo-resistant cells. Collectively, our study sheds new lights on the biological mechanisms underlying the cell-of-origin of leukemia.

2023-11-01 | GSE210923 | GEO

Single-cell chromatin accessibility data using scATAC-seq

Project description:A single hematopoietic stem cell can give rise to all blood cells with remarkable fidelity. Here, we define the chromatin accessibility and transcriptional landscape controlling this process in thirteen primary cell types that traverse the hematopoietic hierarchy. Exploiting the finding that enhancer landscapes better reflect cell identity than mRNA levels, we enable "enhancer cytometry" for accurate enumeration of pure cell types from complex populations. We further reveal the lineage ontogeny of genetic elements linked to diverse human diseases. In acute myeloid leukemia, chromatin accessibility reveals distinctive regulatory evolution in pre-leukemic HSCs (pHSCs), leukemia stem cells, and leukemic blasts. These leukemic cells demonstrate unique lineage infidelity, confirmed by single cell regulomes. We further show that pHSCs have a competitive advantage that is conferred by reduced chromatin accessibility at HOXA9 targets and is associated with adverse patient outcomes. Thus, regulome dynamics can provide diverse insights into human hematopoietic development and disease. Single-cell ATAC-seq of LMPPs, Monocytes, LSCs and Luekemic blast cells.

2016-06-01 | E-GEOD-74310 | biostudies-arrayexpress

Molecular mechanisms in Murine Syngeneic Leukemia Stem Cells

Project description:Cancer treatments usually gain good response, but some tumors relapse frequently. Acute My-eloid Leukemia (AML) is notorious for its robust relapse. This is attributed to the Leukemic Stem Cells (LSCs). We use a murine syngeneic leukemia model, ML23, in search for possible identifi-cation and study of LSCs in syngeneic settings. Hereby, we present prospective isolation of a de-fined LSC sub-population, encompassing the potency to passage disease from mouse to mouse. We further provide molecular insights of whole transcriptome analysis. Importantly, the ML23 LSC sub-population is expressing therapeutic targeted genes and provides a model for research in immune-competent animals.

2023-02-15 | GSE220908 | GEO

Cell quiescence and reprogramming are distinctive features of pre-leukemic stem cells [H2Bgfp]

2023-11-01 | GSE210925 | GEO

Cell quiescence and reprogramming are distinctive features of pre-leukemic stem cells [RNA-seq CTV]

2023-11-01 | GSE210924 | GEO

Transcriptome analysis of AML samples at diagnosis and relapse after Hematopoietic Stem Cell Transplantation (HSCT)

Project description:Transcriptome profiling of Acute Myeloid Leukemia samples. This dataset includes patients with diagnosis of de novo or secondary AML who experienced non-HLA loss disease relapse after allo-HCT, and for whom paired pre- and post-transplant viable leukemic samples were available.

2019-01-29 | E-MTAB-7456 | biostudies-arrayexpress

Transcriptome analysis of AML samples at diagnosis and relapse after Hematopoietic Stem Cell Transplantation (HSCT)

2019-01-31 | E-MTAB-7628 | biostudies-arrayexpress

Transcriptome analysis of AML samples at diagnosis and relapse after Hematopoietic Stem Cell Transplantation (HSCT)

2019-01-31 | E-MTAB-7630 | biostudies-arrayexpress