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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of mouse model of AML - hierarchical maintenance of MLL myeloid leukemia stem cells

ABSTRACT: Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells; The genetic programs that promote retention of self-renewing leukemia stem cells (LSCs) at the apex of cellular hierarchies in acute myeloid leukemia (AML) are not known. In a mouse model of human AML, LSCs exhibit variable frequencies that correlate with the initiating MLL oncogene and are maintained in a self-renewing state by a transcriptional sub-program more akin to that of embryonic stem cells (ESCs) than adult stem cells. The transcription/chromatin regulatory factors Myb, Hmgb3 and Cbx5 are critical components of the program and suffice for Hoxa/Meis-independent immortalization of myeloid progenitors when co-expressed, establishing the cooperative and essential role of an ESC-like LSC maintenance program ancillary to the leukemia initiating MLL/Hox/Meis program. Enriched expression of LSC maintenance and ESC-like program genes in normal myeloid progenitors and poor prognosis human malignancies links the frequency of aberrantly self-renewing progenitor-like cancer stem cells to prognosis in human cancer. Experiment Overall Design: Refer to individual Series Experiment Overall Design: This SuperSeries is composed of the following subset Series: Experiment Overall Design: GSE13690: Gene expression profiling of murine MLL leukemias (whole BM) Experiment Overall Design: GSE13692: Expression profiling of MLL-AF10 myeloid leukemia cellular subsets Experiment Overall Design: GSE13693: Gene expression profiling of normal mouse myeloid cell populations

ORGANISM(S): Mus musculus

SUBMITTER: Tim Somervaille

PROVIDER: E-GEOD-13796 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcription profiling of mouse MLL leukemias (whole BM)

Project description:The genetic programs that promote retention of self-renewing leukemia stem cells (LSCs) at the apex of cellular hierarchies in acute myeloid leukemia (AML) are not known. In a mouse model of human AML, LSCs exhibit variable frequencies that correlate with the initiating MLL oncogene and are maintained in a self-renewing state by a transcriptional sub-program more akin to that of embryonic stem cells (ESCs) than adult stem cells. The transcription/chromatin regulatory factors Myb, Hmgb3 and Cbx5 are critical components of the program and suffice for Hoxa/Meis-independent immortalization of myeloid progenitors when co-expressed, establishing the cooperative and essential role of an ESC-like LSC maintenance program ancillary to the leukemia initiating MLL/Hox/Meis program. Enriched expression of LSC maintenance and ESC-like program genes in normal myeloid progenitors and poor prognosis human malignancies links the frequency of aberrantly self-renewing progenitor-like cancer stem cells to prognosis in human cancer. Experiment Overall Design: Samples are from five separate cohorts of mice where leukemia was initiated using distinct MLL fusion oncogenes: MLL-AF1p (n=9), MLL-AF10 (n=8), MLL-GAS7 (n=5), MLL-AF9 (n=5) and MLL-ENL (n=7). Four normal BM samples were also used as controls.

2009-02-21 | E-GEOD-13690 | biostudies-arrayexpress

Gene expression profiling of murine MLL leukemias (whole BM)

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Hierarchical maintenance of MLL myeloid leukemia stem cells

Project description:Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells The genetic programs that promote retention of self-renewing leukemia stem cells (LSCs) at the apex of cellular hierarchies in acute myeloid leukemia (AML) are not known. In a mouse model of human AML, LSCs exhibit variable frequencies that correlate with the initiating MLL oncogene and are maintained in a self-renewing state by a transcriptional sub-program more akin to that of embryonic stem cells (ESCs) than adult stem cells. The transcription/chromatin regulatory factors Myb, Hmgb3 and Cbx5 are critical components of the program and suffice for Hoxa/Meis-independent immortalization of myeloid progenitors when co-expressed, establishing the cooperative and essential role of an ESC-like LSC maintenance program ancillary to the leukemia initiating MLL/Hox/Meis program. Enriched expression of LSC maintenance and ESC-like program genes in normal myeloid progenitors and poor prognosis human malignancies links the frequency of aberrantly self-renewing progenitor-like cancer stem cells to prognosis in human cancer. This SuperSeries is composed of the SubSeries listed below.

2009-02-06 | GSE13796 | 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.

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Msi2 sustains the MLL leukemia stem cell regulatory program

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Genome-wide expression analysis of wide-type and PirBTM MLL-AF9 LSCs

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Effect of sgRNA-mediated disruption of GLUT1 on gene expression on c-Kit+ MLL::AF9 leukemia cells

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2022-07-28 | GSE209636 | GEO

The H3K4-methyl epigenome regulates MLL leukemia stem cell oncogenic potential

Project description:The genetic programs that maintain leukemia stem cell (LSC) self-renewal and oncogenic potential have been well defined, however the epigenetic landscape that determines their cellular identity and functionality has not been established. We report that LSCs in MLL-associated leukemia are maintained in an epigenetic state defined by relative genome-wide high-level H3K4me3 methylation and low level H3K79me2. LSC differentiation is associated with dynamic reversal of these broad epigenetic profiles and concomitant down-regulation of the LSC maintenance transcriptional program. LSCs also share with embryonic stem cells a large subset of genes with bivalent histone marks related to embryonic development. The histone demethylase KDM5B negatively regulates MLL-induced leukemogenesis demonstrating the crucial role of the H3K4 global methylome for determining leukemia stem cell fate. Investigation of multiple histone modification marks and RNA Pol II in ckit+ and ckit- cells isolated and fractionated from MLL leukemia mice.

2015-06-26 | E-GEOD-60193 | biostudies-arrayexpress

The important role of GPR84 in MLL leukemogenesis

Project description:Beta-catenin signaling is required for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia (AML), yet the upstream regulators that can augment this pathway are unknown. Through genome-wide gene expression analysis and functional studies, we identified an important role for GPR84 in MLL AML. Suppression of GPR84 significantly inhibited cell growth in pre-LSCs, reduced LSC frequency and impaired reconstitution of MLL AML. Furthermore, GPR84 conferred a growth advantage to Hoxa9/Meis1a transduced hematopoietic stem cells (HSCs). Our microarray analysis demonstrated that GPR84 overexpression significantly up-regulated a small set of MLL-fusion targets and beta-catenin co-effectors, and down-regulated a hematopoietic cell cycle inhibitor. These data thus reveal a previously unrecognized role of GPR84 in the maintenance of fully developed AML by sustaining aberrant beta-catenin signaling in LSCs. HSC-derived Hoxa9/Meis1a pre-LSCs were transduced with GPR84 cDNA or empty vector, and replated in methylcellulose supplemented with cytokines. Each group contains triplicate samples.

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