Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MLL-AF9 lates transcriptional initiation in mixed lineage leukemic cells

ABSTRACT: MLL-fusion proteins (MLL-FPs) are believed to maintain gene activation and induce mixed lineage leukemia (MLL) through aberrantly stimulating transcriptional elongation, but the underlying mechanisms are incompletely understood. Here we show that both MLL1 and AF9, one of the major fusion partners of MLL1, mainly occupy promoters and distal intergenic regions, exhibiting chromatin occupancy patterns resembling that of RNA polymerase II (Pol II) in HEL, a human cell line without MLL1 arrangement (MLLr). MLL1 and AF9 only co-regulate over a dozen genes despite of their co-occupancy on thousands of genes. They do not interact with each other, and their chromatin occupancy is also independent of each other. Moreover, AF9 deficiency in HEL cells decreases global TBP occupancy while decreases CDK9 occupancy on a small number of genes, suggesting an accessory role of AF9 in CDK9 recruitment and a possible major role in transcriptional initiation via initiation factor recruitment. Importantly, MLL1 and MLL-AF9 occupy promoters and distal intergenic regions, exhibiting identical chromatin occupancy patterns in MLL cells, and MLL-AF9 deficiency decreased occupancy of TBP and TFIIE on major target genes of MLL-AF9 in iMA9, a murine acute myeloid leukemia (AML) cell line inducibly expressing MLL-AF9, suggesting that it can also regulate initiation. These results suggest that there is no difference between MLL1 and MLL-AF9 with respect to location and size of occupancy sites, contrary to what people have believed, and that MLL-AF9 may also regulate transcriptional initiation in addition to widely-believed elongation.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE231814 | GEO | 2024/07/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

DOT1L complex regulates transcriptional initiation in human cells

Project description:DOT1L, the only H3K79 methyltransferase in human cells and a homolog of the yeast Dot1, normally forms a complex with AF10, AF17 and ENL/AF9, is dysregulated in most of the cases of mixed lineage leukemia (MLL) and is believed to regulate transcriptional elongation without much evidence. Here we show that the depletion of DOT1L reduced the global occupancy without affecting the traveling ratio or the elongation rate of Pol II, suggesting it not a major player in elongation. An examination of general transcription factors (GTFs) binding revealed globally reduced TBP and TFIIA occupancies near promoters after DOT1L loss, pointing to a role in transcriptional initiation. Proteomic studies uncovered that DOT1L regulates transcriptional initiation likely by facilitating the recruitment of TFIID. Moreover, we found that ENL also regulates transcriptional initiation and that DOT1L stimulates H2B monoubiquitination by limiting the recruitment of human SAGA complex. These results advanced current understanding of epigenetic regulation of transcriptional initiation and roles of DOT1L complex in MLL.

2021-06-17 | GSE161367 | GEO

A novel Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia [ChIP-seq]

Project description:Treatment of cells carrying MLL-rearrangements with VTP-50469 (specific Menin-MLL1 inhibitor) displaces Menin from high molecular weight complexes and chromatin genome-wide. Since VTP-50469 block Menin interaction with MLL1 we tested using chip-seq if treatment with VTP-50469 also displaces MLL1 or MLL-fusions from chromatin. We found that the VTP-50469 treatment displaced MLL-fusions from only a subset of MLL-fusion binding sites. Since DOT1L is associated with MLL-AF9 we then tested if displacement of MLL1 also leads to loss of DOT1L association with chromatin on MLL-AF9 binding sites. We found that DOT1L binds to thousands of genes, treatment with VTP-50469 leads to genome wide loss of DOT1L binding including the same subset of MLL-fusion binding sites.

2019-11-06 | GSE127507 | GEO

MLL2, but not MLL1, plays a major role to sustain leukemia survival [RNA-seq]

Project description:We investigated the effect of Mll1, Mll2 and Mll1;Mll2 deletion on gene expression in MLL-AF9-transformed cells.

2017-01-20 | GSE93622 | GEO

ChipSeq of MLL1 in mouse leukemic blast cells

Project description:We performed a chip-seq to determine the binding of MLL1 in mouse leukemic blast cells transduces with MLL-AF9 fusion MLL1 chip-seq in mouse leukemic blast cells

2012-02-22 | E-GEOD-34261 | biostudies-arrayexpress

RNA-seq profiling of murine Tet-off MLL-AF9; NRAS acute myeloid leukemia at different timepoints upon doxycycline-induced MLL-AF9 down-regulation.

Project description:Using an acute myeloid leukemia (AML) mouse model driven by tet-regulated MLL-AF9 (fusion between the gene MLL1 (KMT2A/MLL) and MLLT3 (AF9)) co-expressed with oncogenic NRASG12D (Tet-off MLL-AF9), we investigated the effect of modulating the expression of the MLL-AF9 fusion oncogene on the transcriptome and proteome of established murine AML. Treatment in vitro or in vivo of these Tet-off MLL-AF9 AMLs with doxycycline (DOX) results in the efficient down-regulation of the expression of the driver oncogene MLL-AF9. RNA sequencing analysis was performed on primary Tet-Off MLL-AF9 AML cells obtained from the spleen of leukemic animals and cultured in vitro for either 2 or 4 days in the presence of doxycycline (1μg/ml) (DOX= down-regulation of MLL-AF9) or left untreated (UT).

2021-12-31 | GSE108326 | GEO

MLL2, but not MLL1, plays a major role to sustain leukemia survival [array]

Project description:The MLL1 histone methyltransferase gene undergoes many distinct chromosomal rearrangements to yield poor-prognosis leukemia. The remaining wild-type allele is most commonly, but not always, retained. To what extent the wild-type allele contributes to leukemogenesis is unclear. Here we show using rigorous, independent animal models that endogenous MLL1 is dispensable for MLL-rearranged leukemia. Potential redundancy was addressed by co-deleting the closest paralog, Mll2. Surprisingly, Mll2 deletion alone had a significant impact on survival of MLL-AF9-transformed cells and additional Mll1 loss further reduced viability and proliferation. We show that MLL1/MLL2 collaboration is not through redundancy but regulation of distinct pathways. These findings highlight the relevance of MLL2 as a drug target in MLL-rearranged leukemia and suggest its broader significance in AML. We used microarray to investigate the effect of Mll1 deletion on gene expression in LSC-enriched MLL-AF9 leukemia cells.

2017-01-20 | GSE93621 | GEO

ChipSeq of MLL1 in mouse leukemic blast cells

Project description:We performed a chip-seq to determine the binding of MLL1 in mouse leukemic blast cells transduces with MLL-AF9 fusion

2012-02-22 | GSE34261 | GEO

Chromatin state changes induced by targeted degradation of MLL-AF9 are phenocopied by combined DOT1L and MENIN inhibition. [ChIP-Seq]

Project description:Using ChIP-seq we examined the occupancy changes of various histone marks and chromatin-bound proteins following accute MLL-AF9 degradation in MLL-AF9-HA-FKPB12 transformed human (HCB1) cells. We also examined occupancy changes of various chromatin-bound proteins in human MLL-AF9-HA-FKBP12 transformed cells (HCB1) and MOLM13 cells in response to DOT1L inhibition, Menin-MLL inhibition, and the combination of DOT1L and Menin-MLL inhibition.

2022-03-03 | GSE173599 | GEO

Histone H3K36me2-specific methyltransferase ASH1L promotes the MLL-AF9-induced leukemogenesis

Project description:ASH1L and MLL1 are two histone methyltransferases that facilitate transcriptional activation during normal development. However, the roles of ASH1L and its enzymatic activity in the development of MLL-rearranged leukemias are not fully elucidated in Ash1L gene knockout animal models. In this study, we used an Ash1L conditional knockout mouse model to show that loss of ASH1L in hematopoietic progenitor cells impaired the initiation of MLL-AF9-induced leukemic transformation in vitro. Furthermore, genetic deletion of ASH1L in the MLL-AF9-transformed cells impaired the maintenance of leukemic cells in vitro and largely blocked the leukemia progression in vivo. Importantly, the loss of ASH1L function in the Ash1L-deleted cells could be rescued by wild-type but not the catalytic-dead mutant ASH1L, suggesting the enzymatic activity of ASH1L was required for its function in promoting MLL-AF9-induced leukemic transformation. At the molecular level, ASH1L enhanced the MLL-AF9 target gene expression by directly binding to the gene promoters and modifying the local histone H3K36me2 levels. Thus, our study revealed the critical functions of ASH1L in promoting the MLL-AF9-induced leukemogenesis, which provides a molecular basis for targeting ASH1L and its enzymatic activity to treat MLL-arranged leukemias.

2021-09-07 | GSE183413 | GEO

Proteolytic cleavage by taspase1 and the regulation of the stability of MLL1

Project description:Chromosomal translocations of the Mixed-lineage leukemia 1 (MLL1) gene generate MLL-chimeras that drive pathogenesis of acute myeloid and lymphoid leukemia. The untranslocated MLL1 is a substrate for proteolytic cleavage by the endopeptidase, taspase1, however, the biological significance of MLL1 cleavage by this endopeptidase remains unclear. Here, we demonstrate that taspase1-dependent cleavage of MLL1 results in the destabilization of full-length MLL. Upon loss of taspase1, MLL1 association with chromatin is markedly increased due to the stabilization of its unprocessed version and this stabilization of the uncleaved MLL1 can result in the displacement of MLL-chimeras from chromatin in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating its cleavage, and pharmacological inhibition of CKII blocks taspase1-dependent MLL1 processing, increases MLL1 stability, and results in the displacement of the MLL-chimeras from chromatin. Furthermore, inhibition of CKII in MLL-AF9 mouse model of leukemia delayed leukemic progression in vivo. This study provides insights into the direct regulation of the stability of MLL1, which can be harnessed for targeted therapeutic approaches for the treatment of aggressive MLL leukemia.

2019-01-02 | GSE90762 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data