Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Enhancer remodeling drives MLL oncogene-dependent transcriptional dysregulation in leukemia stem cells [ChIP-seq]

ABSTRACT: Acute myeloid leukemia (AML) with MLL gene rearrangement (MLLr) comprises a cellular hierarchy in which subpopulations of cells with distinct immunophenotypes serve as functional leukemia stem cells (LSCs, c-Kit+) and mature AML cells (mAML, c-Kit-), respectively. They are maintained by a unique gene expression program and chromatin states, which are thought to reflect the actions of cis-regulatory elements with features of enhancers. Here, we delineate the active enhancer landscape and observe pervasive enhancer malfunction in MLLr LSCs. Reconstruction of regulatory networks revealed a master set of hematopoietic transcription factors (TFs). We show that EP300 is an essential transcriptional coregulator with these TFs for maintaining LSC oncogenic potential, as it controls essential gene expression through modulation of H3K27 acetylation and assessments of transcription factor dependencies. Moreover, the EP300 small molecule inhibitor A-485 affects LSC growth by targeting enhancer activity via histone acetyltransferase domain inhibition. Together, these data implicate a perturbed MLLr-specific enhancer accessibility landscape, suggesting the possibility for disruption of the LSC enhancer regulatory axis as a promising therapeutic strategy in AML.

ORGANISM(S): Mus musculus

PROVIDER: GSE199129 | GEO | 2023/02/07

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Enhancer remodeling drives MLL oncogene-dependent transcriptional dysregulation in leukemia stem cells [RNA-seq]

Project description:Acute myeloid leukemia (AML) with MLL gene rearrangement (MLLr) comprises a cellular hierarchy in which subpopulations of cells with distinct immunophenotypes serve as functional leukemia stem cells (LSCs, c-Kit+) and mature AML cells (mAML, c-Kit-), respectively. They are maintained by a unique gene expression program and chromatin states, which are thought to reflect the actions of cis-regulatory elements with features of enhancers. Here, we delineate the active enhancer landscape and observe pervasive enhancer malfunction in MLLr LSCs. Reconstruction of regulatory networks revealed a master set of hematopoietic transcription factors (TFs). We show that EP300 is an essential transcriptional coregulator with these TFs for maintaining LSC oncogenic potential, as it controls essential gene expression through modulation of H3K27 acetylation and assessments of transcription factor dependencies. Moreover, the EP300 small molecule inhibitor A-485 affects LSC growth by targeting enhancer activity via histone acetyltransferase domain inhibition. Together, these data implicate a perturbed MLLr-specific enhancer accessibility landscape, suggesting the possibility for disruption of the LSC enhancer regulatory axis as a promising therapeutic strategy in AML.

2023-02-07 | GSE199786 | GEO

RNA-seq of LSC-like, non-LSC and Mature populations from human AML patient samples

Project description:Acute myeloid leukemia (AML) is a highly heterogeneous disease and reliable detection of leukemic stem cells (LSCs) across genetic subclasses has proven difficult. We aimed to transcriptionally characterize LSCs specifically in monocyte-like AML (Mono-AML) and and primitive-like AML (Prim-AML) samples using cell surface markers. We used CD64+CD11b+ to define Mature blasts and labelled the rest as Immature. To further enrich for LSC-like cells in the Immature blasts in both Mono- and Prim-AML samples, we included GPR56, a marker for LSCs. We performed RNA sequencing on the FACS-sorted LSC-like and Mature cells from 23 AML patients.

2023-03-01 | E-MTAB-11976 | biostudies-arrayexpress

Transcription profiling of human MLL-AF10 myeloid leukemia cellular subsets

Project description:Leukemia cells from mice with MLL-AF10 AML were fractionated into separate sub-populations on the basis of c-kit expression, which correlates with MLL LSC frequency (Somervaille and Cleary, 2006). The sorted AML sub-populations exhibited substantial differences in their frequencies of AML CFCs/LSCs (mean 14-fold) and morphologic features, consistent with a leukemia cell hierarchy with maturation through to terminally differentiated neutrophils. Experiment Overall Design: Leukemic splenocytes from four mice with MLL-AF10 AML were sub-fractionated in to c-kit high and c-kit negative sub-populations by FACS.

2009-02-21 | E-GEOD-13692 | biostudies-arrayexpress

Defective ribosome assembly impairs leukemia progression in a murine model of acute myeloid leukemia

Project description:Despite the advanced understanding of disease mechanisms, the current therapeutic regimens fail to cure most patients with acute myeloid leukemia (AML). In the present study, we address the role of protein synthesis control in AML leukemia stem cell (LSC) function and leukemia propagation. We apply a murine model of mixed-lineage leukemia-rearranged AML to demonstrate that LSCs synthesize more proteins per hour compared with the bulk of leukemia. Using a genetic model that permits inducible and graded regulation of ribosomal subunit joining, we show that defective ribosome assembly leads to a significant survival advantage by selectively eradicating LSCs but not normal hematopoietic stem and progenitor cells. Finally, transcriptomic and proteomic analyses identify a rare subset of LSCs with immature stem cell signature and high ribosome content that underlies the resistance to defective ribosome assembly. Collectively, our study unveils a critical requirement of high protein synthesis rate for LSC function, highlighting ribosome assembly as a therapeutic target in AML.

2024-10-08 | PXD038318 | Pride

Expression profiling of MLL-AF10 myeloid leukemia cellular subsets

2009-02-06 | GSE13692 | GEO

Three-dimensional chromatin landscapes in MLLr AML [Micro-C]

Project description:Rearrangements of the mixed lineage leukemia (MLLr) gene are frequently associated with both pediatric and adult leukemia. However, the treatment options for these aggressive MLLr leukemias are limited due to the genomic complexity and dynamics of 3D structure in oncogene transcription and leukemia development. Here, we use Micro-C and transcriptome profiling to examine the MLLr-driven aberrant 3D genome architecture in gene-edited MLL-AF9 AML samples with biologically matched healthy donors. Recurrent and MLLr-specific alterations in A/B compartments, topologically associating domains and chromatin loops were identified. RNA sequencing in the same AML samples also revealed extensive and recurrent MLLr-specific promoter–enhancer and promoter–silencer loops. Overall, this study highlights the critical regulatory elements and provides rational and effective targeting strategy in MLLr AML.

2024-02-20 | GSE244471 | GEO

Three-dimensional chromatin landscapes in MLLr AML [RNA-Seq]

2024-02-20 | GSE244470 | GEO

Msi2 sustains the MLL leukemia stem cell regulatory program

Project description:Leukemia stem cells (LSCs) are found in most aggressive myeloid diseases and contribute to therapeutic resistance. Genetic and epigenetic alterations cause a dysregulated developmental program in leukemia. The MSI2 RNA binding protein has been previously shown to predict poor survival in leukemia. We demonstrate that the conditional deletion of Msi2 results in delayed leukemogenesis, reduced disease burden and a loss of LSC function. Gene expression profiling of the Msi2 ablated LSCs demonstrates a loss of the HSC/LSC and an increase in the differentiation program. The gene signature from the Msi2 deleted LSCs correlates with survival in AML patients. MSI2’s maintains the MLL self-renewal program by interacting with and retaining efficient translation of Hoxa9, Myc and Ikzf2. We further demonstrate that shRNA depletion of the MLL target gene Ikzf2 also contributes to MLL leukemia cell survival. Our data provides evidence that MSI2 controls efficient translation of the oncogenic LSC self-renewal program and a rationale for clinically targeting MSI2 in myeloid leukemia. RNA-Seq was performed on sorted c-Kit high leukemic cells from 2 Msi2 -/- and 2 Msi2 f/f mice.

2015-01-15 | E-GEOD-64545 | biostudies-arrayexpress

Dormant leukemia stem cells reinforced by chemotherapy drive early treatment failure in acute myeloid leukemia patients [scRNA_PDX]

Project description:Acute myeloid leukemia is characterized by a minor fraction of primitive leukemia stem cells (LSCs) that sustain disease propagation and may be at the origin of late relapse. Yet, LSC contribution to early therapy resistance and AML regeneration remains controversial. We prospectively identified LSCs in NPM1-mutated AML patients and xenografts by means of a microRNA-126 reporter and single cell RNA sequencing, precisely discriminating LSCs from regenerating hematopoiesis, and assessed their longitudinal response to chemotherapy. We here show that chemotherapy resulted in distinct outcomes within AML subpopulations: while the bulk leukemia proliferated and differentiated with expression of oxidative-phosphorylation signatures, persisting miR-126high LSCs enforced protective stemness and dormancy features, along with a generalized inflammatory and senescence-associated response. miR-126high LSCs were enriched at diagnosis in patients with chemotherapy-refractory AML. We derived a novel miR-126high LSC transcriptional signature, which robustly stratified patients for overall survival in large AML cohorts, shining the spotlight on LSCs as determinants of early therapy resistance.

2023-02-06 | GSE185834 | GEO

Dormant leukemia stem cells reinforced by chemotherapy drive early treatment failure in acute myeloid leukemia patients [bulkRNA]

2023-02-06 | GSE185824 | GEO