Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA184036 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR636606.fastq.gz | Fastqsanger.gz | |||
| SRR636607.fastq.gz | Fastqsanger.gz | |||
| SRR636608.fastq.gz | Fastqsanger.gz | |||
| SRR636609.fastq.gz | Fastqsanger.gz | |||
| SRR636610.fastq.gz | Fastqsanger.gz |
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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
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.
2015-12-14 | GSE42990 | GEO
Project description:Acute Myeloid Leukemia (AML) with MLL gene rearrangements demonstrate unique gene expression profiles driven by MLL-fusion proteins. Here, we identify the circadian clock transcription factor SHARP1 as a novel oncogenic target in MLL-AF6 AML, which has the worst prognosis among all subtypes of MLL rearranged AMLs. SHARP1 is expressed solely in MLL-AF6 AML, and its expression is regulated directly by MLL-AF6 / DOT1L. Suppression of SHARP1 induces robust apoptosis of human MLL-AF6 AML cells. Genetic deletion in mice delays the development of leukemia and attenuated leukemia-initiating potential, while sparing normal hematopoiesis. Mechanistically, SHARP1 binds to transcriptionally active chromatin across the genome and activates genes critical for cell survival as well as key oncogenic targets of MLL-AF6. Our findings demonstrate the unique oncogenic role for SHARP1 in MLL-AF6 AML.
2018-04-26 | GSE95511 | GEO
Project description:In this study, we identify MBNL1 as a unique molecular vulnerability across MLL-rearranged leukemias. Through transcriptomic profiling and novel splicing analyses of MLL-rearranged leukemia cell lines following shRNA knockdown of MBNL1, we show that MBNL1 regulates alternative splicing (predominantly intron retention) of genes essential to MLL-rearranged leukemogenesis, such as DOT1L and SETD1A.
2020-03-25 | GSE123441 | GEO
Project description:Background: MLL-rearranged (MLLr) acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) involve reciprocal oncogenic translocations of the KMT2A/KMT2B (MLL1/MLL2) gene on chromosome 11q23 with various translocation partner genes, which yields to chimeric MLL fusion proteins (MLL-FPs). Menin, the protein product of the MEN1 gene, is essential for the leukemogenic activity of MLL-FPs. Revumenib, a small-molecule inhibitor that selectively disrupts the menin-MLL interaction, has recently received FDA approval for clinical use for the treatment of adult and pediatric patients with relapsed or refractory MLLr acute leukemia. Notably, menin also interacts with the AP-1 transcription factor JUND through a conserved sequence identical to that required for MLL-FP binding. Despite this structural similarity, the impact of menin-MLL inhibitors on JUND function has remained unexplored. Results: In this study, we investigated the influence of menin-MLL inhibitors on JUND activity. Quantitative mass spectrometry analysis of MLLr leukemia cells treated with menin-MLL inhibitors demonstrated that they also disrupt menin-JUND protein interactions. Furthermore, CRISPR-mediated inactivation of JUND or pharmacological inhibition using JNK inhibitors synergistically enhanced the anti-leukemic effects of menin-MLL inhibitors, leading to reduced cell proliferation, cell cycle arrest and apoptosis. RNA sequencing and chromatin binding assays revealed that menin-MLL inhibitor treatment increases JUND chromatin occupancy, leading to upregulation of target gene expression and potentially contributing to the development of resistance to menin-MLL inhibitors. Mouse models engrafted with JUND-deficient leukemia cells exhibited reduced tumor burden compared to control mice engrafted with wild type leukemic cells. Conclusion: These findings suggest that targeting JUND activity may significantly enhance the efficacy of menin-MLL inhibitors towards MLLr leukemia cells.
2026-07-28 | PXD067825 | Pride
Project description:Background: MLL-rearranged (MLLr) acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) involve reciprocal oncogenic translocations of the KMT2A/KMT2B (MLL1/MLL2) gene on chromosome 11q23 with various translocation partner genes, which yields to chimeric MLL fusion proteins (MLL-FPs). Menin, the protein product of the MEN1 gene, is essential for the leukemogenic activity of MLL-FPs. Revumenib, a small-molecule inhibitor that selectively disrupts the menin-MLL interaction, has recently received FDA approval for clinical use for the treatment of adult and pediatric patients with relapsed or refractory MLLr acute leukemia. Notably, menin also interacts with the AP-1 transcription factor JUND through a conserved sequence identical to that required for MLL-FP binding. Despite this structural similarity, the impact of menin-MLL inhibitors on JUND function has remained unexplored. Results: In this study, we investigated the influence of menin-MLL inhibitors on JUND activity. Quantitative mass spectrometry analysis of MLLr leukemia cells treated with menin-MLL inhibitors demonstrated that they also disrupt menin-JUND protein interactions. Furthermore, CRISPR-mediated inactivation of JUND or pharmacological inhibition using JNK inhibitors synergistically enhanced the anti-leukemic effects of menin-MLL inhibitors, leading to reduced cell proliferation, cell cycle arrest and apoptosis. RNA sequencing and chromatin binding assays revealed that menin-MLL inhibitor treatment increases JUND chromatin occupancy, leading to upregulation of target gene expression and potentially contributing to the development of resistance to menin-MLL inhibitors. Mouse models engrafted with JUND-deficient leukemia cells exhibited reduced tumor burden compared to control mice engrafted with wild type leukemic cells. Conclusion: These findings suggest that targeting JUND activity may significantly enhance the efficacy of menin-MLL inhibitors towards MLLr leukemia cells.
2026-07-28 | PXD068061 | Pride
Project description:Background: MLL-rearranged (MLLr) acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) involve reciprocal oncogenic translocations of the KMT2A/KMT2B (MLL1/MLL2) gene on chromosome 11q23 with various translocation partner genes, which yields to chimeric MLL fusion proteins (MLL-FPs). Menin, the protein product of the MEN1 gene, is essential for the leukemogenic activity of MLL-FPs. Revumenib, a small-molecule inhibitor that selectively disrupts the menin-MLL interaction, has recently received FDA approval for clinical use for the treatment of adult and pediatric patients with relapsed or refractory MLLr acute leukemia. Notably, menin also interacts with the AP-1 transcription factor JUND through a conserved sequence identical to that required for MLL-FP binding. Despite this structural similarity, the impact of menin-MLL inhibitors on JUND function has remained unexplored. Results: In this study, we investigated the influence of menin-MLL inhibitors on JUND activity. Quantitative mass spectrometry analysis of MLLr leukemia cells treated with menin-MLL inhibitors demonstrated that they also disrupt menin-JUND protein interactions. Furthermore, CRISPR-mediated inactivation of JUND or pharmacological inhibition using JNK inhibitors synergistically enhanced the anti-leukemic effects of menin-MLL inhibitors, leading to reduced cell proliferation, cell cycle arrest and apoptosis. RNA sequencing and chromatin binding assays revealed that menin-MLL inhibitor treatment increases JUND chromatin occupancy, leading to upregulation of target gene expression and potentially contributing to the development of resistance to menin-MLL inhibitors. Mouse models engrafted with JUND-deficient leukemia cells exhibited reduced tumor burden compared to control mice engrafted with wild type leukemic cells. Conclusion: These findings suggest that targeting JUND activity may significantly enhance the efficacy of menin-MLL inhibitors towards MLLr leukemia cells.
2026-07-28 | PXD068056 | Pride
Project description:Background: MLL-rearranged (MLLr) acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) involve reciprocal oncogenic translocations of the KMT2A/KMT2B (MLL1/MLL2) gene on chromosome 11q23 with various translocation partner genes, which yields to chimeric MLL fusion proteins (MLL-FPs). Menin, the protein product of the MEN1 gene, is essential for the leukemogenic activity of MLL-FPs. Revumenib, a small-molecule inhibitor that selectively disrupts the menin-MLL interaction, has recently received FDA approval for clinical use for the treatment of adult and pediatric patients with relapsed or refractory MLLr acute leukemia. Notably, menin also interacts with the AP-1 transcription factor JUND through a conserved sequence identical to that required for MLL-FP binding. Despite this structural similarity, the impact of menin-MLL inhibitors on JUND function has remained unexplored. Results: In this study, we investigated the influence of menin-MLL inhibitors on JUND activity. Quantitative mass spectrometry analysis of MLLr leukemia cells treated with menin-MLL inhibitors demonstrated that they also disrupt menin-JUND protein interactions. Furthermore, CRISPR-mediated inactivation of JUND or pharmacological inhibition using JNK inhibitors synergistically enhanced the anti-leukemic effects of menin-MLL inhibitors, leading to reduced cell proliferation, cell cycle arrest and apoptosis. RNA sequencing and chromatin binding assays revealed that menin-MLL inhibitor treatment increases JUND chromatin occupancy, leading to upregulation of target gene expression and potentially contributing to the development of resistance to menin-MLL inhibitors. Mouse models engrafted with JUND-deficient leukemia cells exhibited reduced tumor burden compared to control mice engrafted with wild type leukemic cells. Conclusion: These findings suggest that targeting JUND activity may significantly enhance the efficacy of menin-MLL inhibitors towards MLLr leukemia cells.
2026-07-28 | PXD068124 | Pride
Project description:FOXM1 Controls Leukemia Stem Cell Fate in MLL-Rearranged AML
| PRJNA515914 | ENA
Project description:We investigated the role of the transcriptional regulators Id2 and E2-2 (encoded by Tcf4) in the context of MLL-rearranged acute myeloid leukemia (AML). Using an AML mouse model driven by a Tet-off inducible MLL-AF9 allele co-expressed with oncogenic NRASG12D, 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 MLL-AF9 AML cells results inhibition of leukemia growth, loss of leukemia stem cell-associated gene expression pattern and induction of differentiation. E2-2 silencing phenocopies Id2 overexpression in MLL-AF9-AML cells. To study the gene expression changes associated with E2-2 depletion in the context of MLL-rearranged AML, RNA sequencing analysis was performed on MLL-AF9;NRAS AML cells transduced with vectors expressing hairpins against E2-2 (shTcf4#654 and shTcf4#3646) or a control hairpin against Renilla luciferase (shRen).
2016-06-29 | GSE80745 | GEO