Conditional modeling of MLL-AF9 induced leukemia revealed a stem cell derived aggressive disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Antoine Peters
PROVIDER: E-GEOD-65384 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
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
Project description:Leukemia initiating cells (LICs) of acute myeloid leukemia (AML) may arise from self-renewing hematopoietic stem cells (HSCs) and from committed progenitors. However, it remains unclear how leukemia-associated oncogenes instruct LIC formation from cells of different origins and if differentiation along the normal hematopoietic hierarchy is involved. Here, using murine models with the driver mutations MLL-AF9 or MOZ-TIF2, we found that regardless of the transformed cell types, myelomonocytic differentiation to the granulocyte macrophage progenitor (GMP) stage is critical for LIC generation. Blocking myeloid differentiation through disrupting the lineage-restricted transcription factor C/EBPa eliminates GMPs, blocks normal granulopoiesis, and prevents AML development. In contrast, restoring myeloid differentiation through inflammatory cytokines “rescues” AML transformation. Our findings identify myeloid differentiation as a critical step in LIC formation and AML development, thus guiding new therapeutic approaches. Primary KSL, CMP, and GMP cells from wildtype controls and C/Ebpa knockouts were used for RNA extraction and hybridization on Affymetrix microarrays. We also compared the microarray samples of leukemic granulocyte macrophage progenitor compartments (L-GMPs) from MLL-AF9 transformed control or cytokine rescued C/EBPa KO leukemic mouse bone marrow and their secondary recipients with those non-Leukemia KSLs and CMPs from MLL-AF9 transduecd KO recipients with no leukemia development.
2015-08-04 | E-GEOD-71687 | biostudies-arrayexpress
Project description:Leukemia initiating cells (LICs) of acute myeloid leukemia (AML) may arise from self-renewing hematopoietic stem cells (HSCs) and from committed progenitors. However, it remains unclear how leukemia-associated oncogenes instruct LIC formation from cells of different origins and if differentiation along the normal hematopoietic hierarchy is involved. Here, using murine models with the driver mutations MLL-AF9 or MOZ-TIF2, we found that regardless of the transformed cell types, myelomonocytic differentiation to the granulocyte macrophage progenitor (GMP) stage is critical for LIC generation. Blocking myeloid differentiation through disrupting the lineage-restricted transcription factor C/EBPa eliminates GMPs, blocks normal granulopoiesis, and prevents AML development. In contrast, restoring myeloid differentiation through inflammatory cytokines “rescues” AML transformation. Our findings identify myeloid differentiation as a critical step in LIC formation and AML development, thus guiding new therapeutic approaches. Primary KSL, CMP, and GMP cells from wildtype controls and C/Ebpa knockouts were used for RNA extraction and hybridization on Affymetrix microarrays. We also compared the microarray samples of leukemic granulocyte macrophage progenitor compartments (L-GMPs) from MLL-AF9 transformed control or cytokine rescued C/EBPa KO leukemic mouse bone marrow and their secondary recipients with those non-Leukemia KSLs and CMPs from MLL-AF9 transduecd KO recipients with no leukemia development.
2014-09-17 | E-GEOD-61468 | biostudies-arrayexpress
Project description:MLL-fusions may induce leukemogenic gene expression programs by recruiting the histone H3K79 methyltransferase to MLL-target promoters. We evaluated gene expression changes after cre-mediated loss of Dot1l in leukemia cells obtained from mice injected with MLL-9 transformed lineage negative bone marrow cells. MLL-AF9 murine leukemia cells carrying two conditional Dot1l alleles were retrovirally transduced with Cre or empty control vector, and gene expression changes were monitored on day 3, 5, and 7 after transduction.
2011-09-12 | E-GEOD-25911 | biostudies-arrayexpress
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
Project description:Next generation DNA sequencing of acute myeloid leukemia (AML) patient samples has revealed novel recurrent mutations while at the same time highlighting the genetic heterogeneity of the disease. These observations suggest that an extraordinarily large number of combinations of mutations can contribute to leukemogenesis. In order to address the question of the contribution of patient genetic background to AML we have developed a model system to generate multiple human leukemias in a single donorâs genetic background. Stepwise RNA-seq data from this model shows that in the context of AML driven by the MLL-AF9 (MA9) oncogene, the genetic background of the donor does not have a detectable effect. Comparison of these model leukemias from multiple single donors to AML patient samples containing MA9 translocations revealed conserved gene expression patterns not previously highlighted in this genetic sub-type. We further demonstrate that the expression of one of these genes, RET, is essential both in vivo and in vitro growth of MA9 AMLs . study of methylome during the development of MLL-AF9 AML
2017-05-02 | E-GEOD-70755 | biostudies-arrayexpress
Project description:We evaluated gene expression changes in murine leukemia caused by retroviral overexpression of MLL-AF9. We compared wild-type (WT) leukemia cells with mutant leukemia cells after cre-mediated inactivation of homozygous conditional alleles for Ezh2 or Eed, both of which are components of the Polycomb Repressive Complex2. For WT cells, 3 biological replicates were hybridized. For Ezh2-null cells, 4 biological replicates were hybridized. For Eed-cells, 3 biological replicates were hybridized.
2012-02-22 | E-GEOD-34959 | biostudies-arrayexpress
Project description:Deletion of AMPK significantly extended the onset of leukemogenesis and depleted leukemia initiating cells (LICs). To identify how AMPK regulates LICs, we performed gene expression profiling of LICs isolated from AMPK wild type leukemic mice or AMPK-deficient leukemic mice. 4 groups were analyzed; 1) Whole leukemia (GFP+) from AMPK WT ( AMPKfl/fl) mice, 2) Whole leukemia (GFP+) from AMPK-deficient ( AMPK?/?l) mice, 3) LICs=L-GMP (GFP+,lin-,c-kit+, CD16/32+,CD34+) cells from AMPK WT ( AMPKfl/fl) mice, 4) LICs=L-GMP (GFP+,lin-,c-kit+, CD16/32+,CD34+) cells from AMPK-deficient ( AMPK?/?l) mice.
2015-01-01 | E-GEOD-64602 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-08-04 | E-GEOD-71691 | biostudies-arrayexpress
Project description:We evaluated gene expression changes in secondary recipient murine leukemia caused by retroviral overexpression of MLL-AF9. We compared wild-type (WT) leukemia cells with mutant leukemia cells after cre-mediated inactivation of a homozygous conditional allele for Ezh2, a component of the Polycomb Repressive Complex2. For WT cells, 4 biological replicates were hybridized. For Ezh2-null cells, 5 biological replicates were hybridized.
2012-02-22 | E-GEOD-34961 | biostudies-arrayexpress