Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA298747 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2648660.fastq.gz | Fastqsanger.gz | |||
| SRR2648661.fastq.gz | Fastqsanger.gz | |||
| SRR2648662.fastq.gz | Fastqsanger.gz | |||
| SRR2648663.fastq.gz | Fastqsanger.gz | |||
| SRR2648664.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 9 |
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Project description:Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a
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Project description:Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a (RNA-Seq)
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Project description:The Hematopoietically-expressed homeobox (Hhex) transcription factor is overexpressed in human myeloid leukemias. Conditional knockout models of murine acute myeloid leukemia (AML) indicate that Hhex maintains leukemia stem cell self-renewal by enabling Polycomb-mediated epigenetic repression of the Cdkn2a tumor suppressor locus, encoding p16Ink4a and p19Arf. However, whether Hhex overexpression also affects hematopoietic differentiation is unknown. To study this, we retrovirally overexpressed Hhex in hematopoietic progenitors. This enabled serial replating of myeloid progenitors, leading to the rapid establishment of IL-3-dependent promyelocytic cell lines. Use of a Hhex-ERT2 fusion protein demonstrated that continuous nuclear Hhex is required for transformation, and structure function analysis demonstrated a requirement of the DNA binding and N-terminal repressive domains of Hhex for promyelocytic transformation. This included the N-terminal Pml interaction domain, although deletion of Pml failed to prevent Hhex-induced promyelocyte transformation, implying other critical partners. Furthermore, deletion of p16Ink4a or p19Arf did not promote promyelocyte transformation, indicating that repression of distinct Hhex target genes is required for this process. Indeed, transcriptome analysis showed that Hhex overexpression resulted in repression of several myeloid developmental genes. To test potential for Hhex overexpression to contribute to leukemic transformation, Hhex-transformed promyelocyte lines were rendered growth factor-independent using a constitutively active IL-3 receptor common b subunit (bcV449E). The resultant cell lines resulted in a rapid promyelocytic leukemia in vivo. Thus Hhex overexpression can contribute to myeloid leukemia via multiple mechanisms including differentiation blockade and enabling epigenetic repression of the Cdkn2a locus.
2018-01-30 | GSE109793 | GEO
Project description:Unlike clustered HOX genes, the role of non-clustered homeobox gene family members in hematopoiesis and leukemogenesis has not been extensively studied. Here we find that the Hematopoietically-expressed Homeobox gene, Hhex, is overexpressed in acute myeloid leukemia (AML) and is essential for the initiation and propagation of MLL-ENL induced AML, but dispensable for normal myelopoiesis, indicating a specific requirement for Hhex for leukemic growth. Loss of Hhex leads to upregulated expression of the tumor suppressors p16INK4a and p19ARF, which are required for growth arrest and myeloid differentiation following Hhex deletion. Mechanistically, we show that Hhex binds to the Cdkn2a locus and is required for H3K27Me3-mediated repression of this locus. Thus, Hhex is a novel therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal.
2016-10-18 | GSE74018 | GEO
Project description:Unlike clustered HOX genes, the role of non-clustered homeobox gene family members in hematopoiesis and leukemogenesis has not been extensively studied. Here we find that the Hematopoietically-expressed Homeobox gene, Hhex, is overexpressed in acute myeloid leukemia (AML) and is essential for the initiation and propagation of MLL-ENL induced AML, but dispensable for normal myelopoiesis, indicating a specific requirement for Hhex for leukemic growth. Loss of Hhex leads to upregulated expression of the tumor suppressors p16INK4a and p19ARF, which are required for growth arrest and myeloid differentiation following Hhex deletion. Mechanistically, we show that Hhex binds to the Cdkn2a locus and is required for H3K27Me3-mediated repression of this locus. Thus, Hhex is a novel therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal.
2016-10-18 | GSE74017 | GEO
Project description:The Hematopoietically-expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of Common Lymphoid Progenitors (CLPs) to lymphoid lineages. However, whether Hhex plays a role in HSC self-renewal and myeloid expansion during hematopoietic stress is unknown. Here we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal. Moreover, Hhex-deleted mice show markedly impaired hematopoietic recovery following myeloablation. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature hematopoietic progenitors. Transcriptome analysis of Hhex-null Lin-Sca+Kit+ (LSK) cells showed that Hhex deletion leads to the deregulation of Polycomb Repressive Complex 2 (PRC2) target genes, including an upregulation of Cdkn2a locus, encoding the cell cycle repressors p16Ink4a and p19Arf. Indeed, loss of Cdkn2a restored Hhex-null blast colony replating in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to repress Cdkn2a to enable continued self-renewal and response to hematopoietic stress.
2017-05-22 | GSE86209 | GEO
Project description:The transcriptional activating and repressive functions performed by Trithorax and Polycomb group complexes, respectively, are critical for to maintain cellular fates in ontogeny and in cancer. Here we report that leukemias initiated by a Trithorax-related oncogene, MLL-AF9, depend upon the Polycomb Repressive Complex 2 (PRC2) to sustain a transformed cellular state. RNAi mediated suppression of PRC2 subunits is sufficient to inhibit proliferation of MLL-AF9 leukemias, with little impact on growth of non-transformed cells. This requirement is partly due to PRC2-mediated transcriptional repression of several anti-self-renewal regulators, including Cdkn2a. These results suggest that, unlike the classical antagonism generally observed between Polycomb and Trithorax group proteins during development, the activities of these two pathways can cooperate to promote myeloid neoplasia. In order to understand downstream targets of PRC2 complex in MLL-AF9 leukemia, we performed array in murine MLL-AF9/NrasG12D cell line under the condition that two subunits of PRC2(Eed and Suz12) were suppressed by using shRNAs.
2013-07-01 | E-GEOD-34183 | biostudies-arrayexpress
Project description:We have cloned and characterized a fusion gene NUP98/HHEX1 resulting from t(7;10) from a patient with acute myeloid leukemia (AML). As NUP98/HHEX acts as an aberrant transcriptional activator, putative targets were searched upon transient expression of the fusion in primary murine bone marrow cells. Experiment Overall Design: Murine bone marrow cells were transduced with a retrovirus (MSCV-IRES-GFP, MIG) expressing either NUP98/HHEX or NUP98/HOXA9 (or the empty vector), mRNA was isolated after 72h. Each experiment was performed in triplicates.
2008-06-11 | E-GEOD-10909 | biostudies-arrayexpress
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
Project description:We have cloned and characterized a fusion gene NUP98/HHEX1 resulting from t(7;10) from a patient with acute myeloid leukemia (AML). As NUP98/HHEX acts as an aberrant transcriptional activator, putative targets were searched upon transient expression of the fusion in primary murine bone marrow cells. Keywords: Comparative analysis of NUP98/HHEX, NUP98/HOX vs. MIG (empty virus) in primary bone marrow cells
2008-04-01 | GSE10909 | GEO