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Conditional modeling of MLL-AF9 induced leukemia revealed a stem cell derived aggressive disease [Microarray]

ABSTRACT: To address the impact of cellular origin on AML, we generated an inducible transgenic mouse model for MLL-AF9 driven leukemia. MLL-AF9 expression in long-term hematopoietic stem cells (LT-HSCs) in vitro resulted in unprecedented clonogenic growth and expression of genes involved in migration and invasion. In vivo, some LT-HSC-derived AMLs were particularly aggressive with extensive tissue infiltration, chemo-resistance and expression of genes related to epithelial-mesenchymal transition (EMT) in solid cancers. Knockdown of the EMT regulators Zeb1 and Tcf4 significantly reduced leukemic blast invasion. By classifying mouse and human leukemia according to Evi1/EVI1and Erg/ERG expression, reflecting aggressiveness and cell-of-origin and performing comparative transcriptomics we identified numerous EMT-related genes that were significantly associated with poor overall survival of AML patients. RNA from primary cells as well as doxycyclin treated cells from immortalized LT-HSC and GMP (Granulocyte macrophage progenitor) celllines was isolated for expression profiling on Affymetrix gene arrays.

ORGANISM(S): Mus musculus

SUBMITTER: Antoine Peters

PROVIDER: E-GEOD-65382 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Conditional modeling of MLL-AF9 induced leukemia revealed a stem cell derived aggressive disease [RNA-Seq]

Project description:To address the impact of cellular origin on AML, we generated an inducible transgenic mouse model for MLL-AF9 driven leukemia. MLL-AF9 expression in long-term hematopoietic stem cells (LT-HSCs) in vitro resulted in unprecedented clonogenic growth and expression of genes involved in migration and invasion. In vivo, some LT-HSC-derived AMLs were particularly aggressive with extensive tissue infiltration, chemo-resistance and expression of genes related to epithelial-mesenchymal transition (EMT) in solid cancers. Knockdown of the EMT regulators Zeb1 and Tcf4 significantly reduced leukemic blast invasion. By classifying mouse and human leukemia according to Evi1/EVI1and Erg/ERG expression, reflecting aggressiveness and cell-of-origin and performing comparative transcriptomics we identified numerous EMT-related genes that were significantly associated with poor overall survival of AML patients. RNA from FACS sorted bone marrow subpopulations was isolated, RNA-sequencing libraries were prepared and sequenced on an Illumina HiSeq 2000. Reads mapping to RefSeq transcripts were counted.

2016-06-27 | E-GEOD-65383 | biostudies-arrayexpress

MLL-AF9 Expression in Hematopoietic Stem Cells Drives a Highly Invasive AML Expressing EMT-Related Genes Linked to Poor Outcome [Microarray]

2016-06-27 | GSE65382 | GEO

MLL-AF9 Expression in Hematopoietic Stem Cells Drives a Highly Invasive AML Expressing EMT-Related Genes Linked to Poor Outcome [RNA-Seq]

2016-06-27 | GSE65383 | GEO

Transcription profiling of mouse hematopoietic cells (GMP, CMP, CLP and HSC), FACS sorted from wild type and Mll-AF9 knock-ins

Project description:The pathways by which oncogenes, such as MLL-AF9, initiate transformation and leukemia in humans and mice are incompletely defined. In a study of target cells and oncogene dosage, we found that Mll-AF9, when under endogenous regulatory control, efficiently transformed LSK (Lin- Sca1+ c-kit+) stem cells while committed granulocyte-monocyte progenitors (GMPs) were transformation-resistant and did not cause leukemia. Mll-AF9 was expressed at higher levels in hematopoietic stem (HSC) than GMP cells. Mll- AF9 gene dosage effects were directly shown in experiments where GMPs were efficiently transformed by the high dosage of Mll-AF9 resulting from retroviral transduction. Mll-AF9 up-regulated expression of 196 genes in both LSK and progenitor cells, but to higher levels in LSKs than in committed myeloid progenitors. Experiment Overall Design: Comparison of gene expression profiles among four types of hematopoietic cells (GMP, CMP, CLP and HSC), FACS sorted from wild type and Mll-AF9 knock-in mice. The goal was to identify genes differentially expressed in each Mll-AF9 cell type compared to the corresponding wild type cells.

2008-04-07 | E-GEOD-10627 | biostudies-arrayexpress

The Polycomb Repressive Complex 2 Is Required For MLL-AF9 Leukemia

Project description:This SuperSeries is composed of the following subset Series: GSE34959: Expression profiling of primary wild type (WT), Ezh2-null and Eed-null murine MLL-AF9 AML GSE34961: Expression profiling of secondary wild type (WT) and Ezh2-null murine MLL-AF9 AML GSE34962: Epigenetic profiling of WT and Ezh2-null MLL-AF9 murine leukemic cells Refer to individual Series

2012-02-22 | E-GEOD-34963 | biostudies-arrayexpress

POLR2M-mediated paused transcription silences tumor suppressor MIR139 in MLL-AF9 AML

Project description:MIR139 is a critical tumor suppressor and commonly silenced in human cancer, including acute myeloid leukemia (AML). Here, we found that depletion of identified MIR139 targets affects AML outgrowth. We unraveled the mechanism of MIR139 gene inactivation in AML expressing the Mixed-Lineage Leukemia (MLL)-AF9 oncogene. Epigenetic analyses revealed two well-conserved putative enhancer regions in close proximity of transcriptional start sites (TSS) of MIR139. These regions were silenced by the Polycomb-Repressive Complex-2 (PRC2) downstream of MLL-AF9. Genomic deletion of these regions abolished MIR139 transcriptional regulation in normal and oncogenic conditions. Genome-wide knockout screens revealed the transcriptional pausing factor of RNA Polymerase-II, POLR2M, as a critical MIR139-silencing factor. Furthermore, direct POLR2M binding to the MIR139 TSS induced paused transcription, which was abrogated upon PRC2 inhibition. We present evidence for an oncogenic POLR2M-mediated MIR139 silencing mechanism, downstream of MLL-AF9 and PRC2. Together, our findings highlight the importance of POLR2M-mediated paused transcription in AML.

2021-11-11 | PXD022488 | Pride

Expression data from human hematopoietic stem and progenitor compartments from patients with acute myeloid leukemia with monosomy 7 and healthy controls

Project description:We applied a novel approach of parallel transcriptional analysis of multiple, highly fractionated stem and progenitor populations in a genetically defined subset of AML (AML with monosomy 7). We isolated phenotypic long-term HSC (LT-HSC), short-term HSC (ST-HSC), and committed granulocyte-monocyte progenitors (GMP) from individual patients with AML, and measured gene expression profiles of each population, and in comparison to their phenotypic counterparts from age-matched healthy controls. Bone marrow samples from AML patients bearing monosomy 7 and age-matched healthy controls were used in this study. Hematopoietic stem and progenitor compartments were purified by multiparameter-high speed fluorescence-activated cell sorting (FACS) from CD34+ enriched bone marrow to isolate LT-HSC (Lin-/CD34+/CD38-/CD90+), ST-HSC (Lin-/CD34+/CD38-/CD90-), and GMP (Lin-/CD34+/CD38+/CD123+/CD45R+).

2012-09-05 | E-GEOD-35010 | biostudies-arrayexpress

Cell of origin determines clinically relevant subtypes of MLL-rearranged AML

Project description:MLL-fusion proteins can induce acute myeloid leukemias (AML) from either hematopoietic stem cells (HSC) or granulocyte macrophage progenitors (GMP), but it remains unclear if the cell of origin influences the biology of the resultant leukemia. MLL-AF9 transduced single HSC or GMP could be continuously replated, but HSC-derived clones were more likely than GMP-derived clones to initiate AML in mice. Leukemia stem cells derived from either HSC or GMP had a similar immunophenotype consistent with a maturing myeloid cell (LGMP). Gene expression analyses demonstrated that LGMP inherited gene expression programs from the cell of origin including high-level Evi-1 expression in HSC derived LGMP. The gene expression signature of LGMP derived from HSC was enriched in poor prognosis human MLL-rearranged AML in three independent data sets. Moreover, global 5’-mC levels were elevated in HSC-derived leukemias as compared to GMP-derived leukemias. This mirrored a difference seen in 5-mC between MLL-rearranged human leukemias that are either EVI1-positive or EVI1-negative. Finally, HSC derived leukemias were more resistant to chemotherapy than GMP-derived leukemias. These data demonstrate that the cell of origin influences the gene expression profile, the epigenetic state, and the drug response in AML, and that these differences can account for clinical heterogeneity within a molecularly defined group of leukemias. Differential DNA methylation between of LSC isolated from murine HSC and GMP derived AMLs

2013-01-09 | E-GEOD-43333 | biostudies-arrayexpress

RNA-seq profiling of murine Tet-off MLL-AF9; NRAS acute myeloid leukemia at different timepoints upon doxycycline-induced MLL-AF9 down-regulation.

Project description:Using an acute myeloid leukemia (AML) mouse model driven by tet-regulated MLL-AF9 (fusion between the gene MLL1 (KMT2A/MLL) and MLLT3 (AF9)) co-expressed with oncogenic NRASG12D (Tet-off MLL-AF9), we investigated the effect of modulating the expression of the MLL-AF9 fusion oncogene on the transcriptome and proteome of established murine AML. Treatment in vitro or in vivo of these Tet-off MLL-AF9 AMLs with doxycycline (DOX) results in the efficient down-regulation of the expression of the driver oncogene MLL-AF9. RNA sequencing analysis was performed on primary Tet-Off MLL-AF9 AML cells obtained from the spleen of leukemic animals and cultured in vitro for either 2 or 4 days in the presence of doxycycline (1μg/ml) (DOX= down-regulation of MLL-AF9) or left untreated (UT).

2021-12-31 | GSE108326 | GEO

RNA sequencing expression analysis of murine Tet-off MLL-AF9;NRAS acute myeloid leukemia cells over-expressing Id2 and upon MLL-AF9 withdrawal

Project description:We investigated the role of the transcriptional regulator Id2 in the context of MLL-rearranged acute myeloid leukemia (AML). Using an AML mouse model driven by tet-regulated MLL-AF9 co-expressed with oncogenic NRASG12D (Tet-off MLL-AF9), we demonstrated that MLL-AF9 regulates the E protein pathway by suppressing Id2, while activating the expression of its target E2-2. Moreover, we found that Id2 over-expression in Tet-Off MLL-AF9 AML cells in vitro partially phenocopies MLL-AF9 depletion and results inhibition of leukemia growth, loss of leukemia stem cell-associated gene expression pattern and induction of differentiation. To compare gene expression changes associated with enforced Id2 expression and MLL-AF9 withdrawal, RNA sequencing analysis was performed on Tet-off MLL-AF9 cells transduced with an Id2 over-expressing or a control vector, or upon MLL-AF9 dox-inducible knock-down. Primary AMLs driven by Tet-off inducible MLL/AF9 expression linked to dsRED reporter, in association with oncogenic NRASG12D (Tet-off MLL-AF9) were generated by reconstituting lethally irradiated congenic mice with foetal liver cells co-transduced with a Tet-Off-MLL-AF9-dRED retroviral vector and a second vector co-expressing NRASG12D together with the Tet-Off responsive transcriptional activator. RNA sequencing analysis sequencing analysis was performed on Tet-Off MLL-AF9/dsRED+ AML cells treated in vitro with doxycycline (DOX) for 4 days to inactivate MLL-AF9 expression or left untreated (UT). For the Id2 over-expression experiment, Tet-Off MLL-AF9/dsRED+ AML cells were transduced in vitro with an Id2-GFP or a control-GFP retroviral vector. Viable GFP-positive cells were FACS-sorted 2 days after transduction and used for RNA sequencing analysis.

2016-06-29 | E-GEOD-68462 | biostudies-arrayexpress

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