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Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia

ABSTRACT: Here we show that pan-haematopoietic ERG expression driven by the Vav promoter induces an early progenitor myeloid leukemia in transgenic mice. Integrated genome-scale analysis of gene expression and ERG binding profiles revealed that ERG activates a transcriptional program similar to human AML stem/progenitor cells and human AML with high ERG expression. We further show that ERG induces expression of the Pim1 kinase oncogene through a novel enhancer element validated in transgenic mice, and Pim1 inhibition disrupts growth and induces apoptosis of ERG-driven leukemic cells. In addition, ERG indirectly induces the RAS pathway and direct RAS inhibition by a RAS inhibitor blocks growth of leukemia cells in vitro and in vivo. Thus, integrative genomic analysis of transgenic ERG leukemias reveals mechanisms and potential therapeutic targets of high ERG expressing AML.

ORGANISM(S): Mus musculus

PROVIDER: GSE46554 | GEO | 2013/08/30

SECONDARY ACCESSION(S): PRJNA201677

REPOSITORIES: GEO

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Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia

Project description:Here we show that pan-haematopoietic ERG expression driven by the Vav promoter induces an early progenitor myeloid leukemia in transgenic mice. Integrated genome-scale analysis of gene expression and ERG binding profiles revealed that ERG activates a transcriptional program similar to human AML stem/progenitor cells and human AML with high ERG expression. We further show that ERG induces expression of the Pim1 kinase oncogene through a novel enhancer element validated in transgenic mice, and Pim1 inhibition disrupts growth and induces apoptosis of ERG-driven leukemic cells. In addition, ERG indirectly induces the RAS pathway and direct RAS inhibition by a RAS inhibitor blocks growth of leukemia cells in vitro and in vivo. Thus, integrative genomic analysis of transgenic ERG leukemias reveals mechanisms and potential therapeutic targets of high ERG expressing AML. Spleen cells were fixed with 1% formaldehyde and ChIP assays were performed as previously described (Wilson NK et al., 2010 Cell Stem Cell) using polyclonal antibodies against ERG-1/2/3 (clone C-17, Sc354X, Santa Cruz) and control nonspecific rabbit IgG (I5006, Sigma).

2013-08-30 | E-GEOD-46554 | biostudies-arrayexpress

Overexpression of ERG in cord blood progenitors promotes expansion and recapitulates molecular signatures of high ERG leukemias

Project description:High expression of the ETS family transcription factor ERG is associated with poor clinical outcome in acute myeloid leukemia (AML) and acute T-cell lymphoblastic leukemia (T-ALL). In murine models, high ERG expression induces both T-ALL and AML. However, no study to date has defined the effect of high ERG expression on primary human hematopoietic cells. In the present study, human CD34+ cells were transduced with retroviral vectors to elevate ERG gene expression to levels detected in high ERG AML. RNA sequencing was performed on purified populations of transduced cells to define the effects of high ERG on gene expression in human CD34+ cells. Integration of the genome-wide expression data with other data sets revealed that high ERG drives an expression signature that shares features of normal hematopoietic stem cells, high ERG AMLs, early T-cell precursor-ALLs and leukemic stem cell signatures associated with poor clinical outcome. Functional assays linked this gene expression profile to enhanced progenitor cell expansion. These results support a model whereby a stem cell gene expression network driven by high ERG in human cells enhances the expansion of the progenitor pool, providing opportunity for the acquisition and propagation of mutations and the development of leukemia.

2014-10-31 | GSE53665 | GEO

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

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 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.

2016-06-27 | E-GEOD-65382 | biostudies-arrayexpress

EVI1 drives leukemogenesis through aberrant activation of ERG

Project description:Chromosomal rearrangements involving EVI1 (MECOM) define a subtype of acute myeloid leukemia (AML) that is associated with a two-year survival rate of <10%. Gene regulatory functions of EVI1 are largely elusive and no targeted therapeutics exist. We developed experimentally tractable murine and human leukemia models that recapitulate phenotypic and transcriptional features of EVI1-rearranged AML and enable large-scale loss-of-function screens. We characterize EVI1-controlled transcriptional programs in cell culture and in vivo, perform CRISPR screens and identify the ETS-related transcription factor ERG as the only gene that is specifically required for EVI1-driven AML. ERG is transcriptionally activated by EVI1 and overexpressed in EVI1-rearranged AML patients. ERG suppression selectively induces terminal differentiation of leukemia cells. EVI1 becomes dispensable for leukemia cells upon ectopic expression of ERG, indicating that key functions of EVI1 are mediated through aberrant activation of ERG. Interfering with this regulatory axis may therefore provide new entry points for rational therapies.

2022-10-11 | GSE195497 | GEO

High ERG expression in human HSPCs promotes progenitor but not stem cell proliferation and molecular signatures that are enriched in high ERG leukemia.

Project description:ERG is an Ets-transcription factor required for normal blood stem cell development. High ERG expression in acute myeloid leukemia (AML) and acute T-cell lymphoblastic leukemia (T-ALL) is associated with a stem cell signature and poor prognosis. In murine over-expression models, human ERG is a potent oncogene that induces both T-ALL and AML. However the functional and molecular consequences of high ERG expression in normal hematopoietic stem/progenitors (HSPCs), and how this contributes to leukemia development, are unknown. Here we show that retroviral transduction of ERG into human CD34+ cells and maintenance of ERG at levels present in high ERG AML results in altered myeloid and T cell differentiation and an increase in the self-renewal capacity of transduced progenitors but not the more primitive stem cell compartment. Integrated analysis of genome-wide expression in high ERG CD34+ and ERG binding profiles in HSPCs revealed that these functional characteristics were accompanied by an expression signature that was enriched in normal HSCs, high ERG AMLs, early T-cell precursor (ETP)-ALLs and leukemic stem cell signatures associated with poor clinical outcome. The proliferative advantage of high ERG progenitors may provide a cellular context for the acquisition and propagation of mutations that contribute to the pathogenesis of leukaemia. RNA sequencing in ERG overexpressing human CD34+ cells

2014-10-31 | E-GEOD-53665 | biostudies-arrayexpress

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

AML1-ETO induced leukemia stem cell self-renewal depends on Plcg1

Project description:High-resolution proteomic analysis of acute myeloid leukemia (AML) stem cells identified phospholipase C- and Ca++-signaling pathways to be differentially regulated in AML1-ETO (AE) driven leukemia. Phospholipase C gamma 1 (Plcg1) could be identified as a direct target of the AE fusion. Genetic Plcg1 inactivation abrogated disease initiation by AE, reduced intracellular Ca++-release and inhibited AE-driven self-renewal programs. In AE-induced leukemia, Plcg1 deletion significantly reduced disease penetrance, number of leukemia stem cells and abrogated leukemia development in secondary recipient hosts. In human AE-positive leukemic cells inactivation of Plcg1 reduced colony formation and AML development in vivo. In contrast, Plcg1 was dispensable for maintenance of murine and human hematopoietic stem- and progenitor cells (HSPCs). Pharmacologic inhibition of Ca++-signaling downstream of Plcg1 resulted in impaired proliferation and self-renewal capacity in AE-driven AML. Thus, the Plcg1 pathway represents a novel specific vulnerability of AE-driven leukemia and poses an important new therapeutic target.

2022-01-12 | PXD011251 | Pride

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

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

Oncogenic RAS primes primary acute myeloid leukemia blasts for differentiation

Project description:RAS mutations are frequently found among AML patients, generating a constitutively active signaling protein changing cellular proliferation, differentiation and apoptosis. We previously showed that treatment of AML patients with high-dose cytarabine (HDAC) is preferentially beneficial for those with an oncogenic RAS mutation. By applying a murine AML model, we could ascribe this effect to a RAS-driven, p53-dependent induction of differentiation. Here, we sought to confirm the correlation between RAS status and differentiation of blasts obtained from AML patients. The expression signature of primary AML blasts expressing oncogenic RAS where compared to blasts with wtRAS. Blasts where obtained from peripheral blood or bone marrow samples from patients with CBFbeta-MYH11 translocations and with or without an additional NRAS point mutation. As a reference, the Kasumi-1 acute myeloid leukemia cell line was used.

2015-11-20 | E-MTAB-2090 | biostudies-arrayexpress

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