Id2 and E proteins orchestrate the initiation and maintenance of MLL-rearranged acute myeloid leukemia
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ABSTRACT:
PROVIDER: PRJNA282885 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2005780.fastq.gz | Fastqsanger.gz | |||
| SRR2005800_1.fastq.gz | Fastqsanger.gz | |||
| SRR2005800_2.fastq.gz | Fastqsanger.gz | |||
| SRR2005781.fastq.gz | Fastqsanger.gz | |||
| SRR2005791.fastq.gz | Fastqsanger.gz |
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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.
2016-06-29 | GSE68462 | GEO
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
Project description:We investigated the role of the transcriptional regulator Id2 in the context of MLL-rearranged acute myeloid leukemia (AML). Using an Id2/GFP-reporter mouse model of MLL-AF9-driven AML, we showed that Id2 is expressed heterogeneously across the leukemic population. Moreover, differential expression of Id2 and the stemness marker Kit defines subsets of AML cells with different leukemogenic properties with lower levels of Id2 associated with enrichment in leukemia stem cell potential. To define gene expression patterns associated with distinct endogenous levels of Id2 and higher LSC potential, RNA sequencing analysis was performed on FACS-sorted KitHIâId2HI (BM_Kplus-Iplus), KitHIâId2LOW(BM_Kplus-Iminus), KitLOWâId2HI (BM_Kminus-Iplus) and KitLOWâId2LOW (BM_Kminus-Iminus) MLL-AF9-cherry+ AML cells obtained from bone marrow of terminally sick mice. Primary MLL-AF9+ AMLs were generated by reconstituting lethally irradiated congenic mice with foetal liver cells obtained from Id2-GFP reporter mice and transduced with a retroviral vector co-expressing MLL-AF9 and the cherry reporter protein. KitHighâId2High, KitHighâId2Low, KitLowâId2High and KitLowâId2Low MLL-AF9/cherry+ AML cells obtained from bone marrow of terminally sick primary recipients were FACS-sorted and used for RNA sequencing analysis (3 samples/subset).
2016-06-29 | E-GEOD-68461 | biostudies-arrayexpress
Project description:We investigated the role of the transcriptional regulator Id2 in the context of MLL-rearranged acute myeloid leukemia (AML). Using an Id2/GFP-reporter mouse model of MLL-AF9-driven AML, we showed that Id2 is expressed heterogeneously across the leukemic population. Moreover, differential expression of Id2 and the stemness marker Kit defines subsets of AML cells with different leukemogenic properties with lower levels of Id2 associated with enrichment in leukemia stem cell potential. To define gene expression patterns associated with distinct endogenous levels of Id2 and higher LSC potential, RNA sequencing analysis was performed on FACS-sorted KitHI–Id2HI (BM_Kplus-Iplus), KitHI–Id2LOW(BM_Kplus-Iminus), KitLOW–Id2HI (BM_Kminus-Iplus) and KitLOW–Id2LOW (BM_Kminus-Iminus) MLL-AF9-cherry+ AML cells obtained from bone marrow of terminally sick mice.
2016-06-29 | GSE68461 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-06-29 | E-GEOD-68463 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-06-29 | GSE68463 | GEO
Project description:Acute Myeloid Leukemia (AML) is associated with a number of genetic and epigenetic events that result in malignant transformation of hematopoietic cells. In particular, transcription factors essential for normal hematopoiesis and stem cell function are often found mutated leading to the formation of leukemic stem cells and the accumulation of immature blasts. Among them, translocations involving the mixed lineage leukemia (MLL) gene at chromosome band 11q23 are one of the most commonly events (~10 %) and is associated with poor prognosis in human leukemias. Whereas the downstream effects of MLL-fusion proteins are well established, the modes on which these effects are mediated are still unclear and whether MLL-fusion proteins are dependent on other transcriptional regulators or act alone remains elusive. To investigate this we searched gene expression profiles from patients with MLL-rearranged AML compared with normal hematopoietic progenitor cells for transcriptional regulators and found targets of C/EBPα to be up-regulated in the AML samples, suggesting that C/EBPα might collaborate with MLL-fusion proteins in the initial transformation process. We could show that transformation by MLL-fusion proteins is dependent on C/EBPα activity both in early progenitors as well as in GMPs. In contrast, C/EBPα was found to be indispensable in an already established leukemia. These finding led us to study the early transcriptional changes induced by MLL-ENL expression and we identified a combined C/EBPα / MLL-ENL transcriptional signature. Collectivly, our data shows that C/EBPα configure a proper chromatin state required for MLL-fusions to induce malignant transformation. Histone modification profiles (H3K4me3 and H3K27me3) in haematopoietic progenitor cells (preGM, wild type and Cebpa knock out), and C/EBPα binding in GMP cells
2013-12-10 | E-GEOD-47003 | biostudies-arrayexpress
Project description:WIN Site inhibitors bind the WIN Site of WDR5 resulting in decreased transcription of WDR5 target genes, many of which encode components of the protein synthesis machinery. In this study, we determined proteome alterations in an MLL-rearranged leukemia cell line treated for either 24 or 72 hours with a WIN Site inhibitor. The data from these studies, along with Ribo-Seq, RNA-Seq, and CRISPR screen experiments, guided us in assembling a collection of compounds that, when combined with WIN Site inhibitor, synergistically inhibit growth of MLL-rearranged leukemia cells.
2023-07-04 | PXD035129 | Pride
Project description:Infant and adult MLL-rearranged (MLLr) leukemia represents a disease with few treatment options and a dismal prognosis. Here, we present an in-depth proteomic characterization of in utero-initiated and adult-onset MLLr leukemia in a mouse model of MLL-ENL-mediated leukemogenesis. We characterize early proteomic events of MLL-ENL-mediated transformation in fetal and adult progenitors.
2024-04-02 | PXD042249 | Pride
Project description:TET1, the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), was first identified as a partner gene in MLL-rearranged leukemia, but its definitive pathological role in leukemia is unclear. The down-regulation of all three TET genes and loss-of-function mutations of TET2 have been frequently observed in various cancers, and it was thought that they all play tumor-suppressor roles in tumorigenesis. Here we show that TET1 is likely a direct target of MLL and significantly up-regulated in MLL-rearranged leukemia, associated with an increased level of 5hmC. Our further in vitro and in vivo studies demonstrate that Tet1 plays an indispensable oncogenic role in MLL-rearranged leukemia, through cooperating with MLL fusion proteins in regulating their co-targets including the Hoxa/Meis1/Pbx3/Flt3 genes. Our data delineate a MLL-fusion/Tet1/Hoxa/Meis1/Pbx3/Flt3 signaling axis in MLL-rearranged leukemia, and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease. We report genome-wide 5hmC enrichment profiles and RNA-Seq gene expression in MLL-AF9 transformed and control mouse bone marrow mononuclear cells. These 5hmC profiles are derived from selctive chemical labeling and enrichment of 5hmC containing genomic DNA fragments, while the RNA-Seq expression profiles are generated from polyA enriched RNA
2015-12-14 | E-GEOD-42990 | biostudies-arrayexpress