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

ABSTRACT: Using SLAM-seq we examined the nascent transcriptional changes following MLL-AF9 degradation in MLL-AF9-HA-FKBP12 transformed hCD34+ cells (HCB1) after 15, 30, 60, and 120 minutes

ORGANISM(S): Homo sapiens

PROVIDER: GSE173571 | GEO | 2022/03/03

REPOSITORIES: GEO

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

Project description:Using ATAC-seq we examined changes in chromatin accessibility following MLL-AF9 degradation in MLL-AF9-HA-FKBP12 transformed hCD34+ cells (HCB1) after 180 minutes.

2022-03-03 | GSE189098 | GEO

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

Project description:Using PRO-seq we examined nascent transcriptional changes and RNA Pol II pausing following MLL-AF9 degradation in MLL-AF9-HA-FKBP12 transformed hCD34+ cells (HCB1) after 15, 30, and 180 minutes

2022-03-03 | GSE189105 | GEO

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

Project description:Using RNA-seq we examined the transcriptional changes following MLL-AF9 degradation in MLL-AF9-HA-FKPB12 transformed murine (BM2222) and human (HCB1) cells. We also examined transcriptional changes 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. Lastly we assessed gene expression in murine neutrophils isolated directly from mice.

2022-03-03 | GSE173574 | 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

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

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

| PRJNA726187 | ENA

Effect of Menin cKO on MLL-AF9 transformed cells

Project description:We determined the effect of conditional deletion of Menin in MLL-AF9 transformed leukemia cells

2018-08-01 | GSE117933 | GEO

POLR2M-mediated paused transcription silences tumor suppressor MIR139 in MLL-AF9 AML

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

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

RNA sequencing expression analysis of murine Tet-off MLL-AF9;NRAS acute myeloid leukemia cells over-expressing Id2 and upon MLL-AF9 withdrawal

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

Controlled MLL-AF9 Expression in Human Induced Pluripotent Stem Cells Reveals MLL-AF9-specific Oncogene Program [hiMLLAF9_scRNAseq]

Project description:A t(9;11)(p22;q23) translocation produces the MLL-AF9 fusion protein, which is found in up to 25% of de novo AML cases in children. Despite major advances, obtaining a comprehensive under-standing of context-dependent MLL-AF9-mediated gene programs during early hematopoiesis is challenging. Here, we generated a human inducible pluripotent stem cell (hiPSC) model with a doxycycline dose-dependent MLL-AF9 expression. We exploited MLL-AF9 expression as an onco-genic hit to uncover epigenetic and transcriptomic effects on iPSC-derived hematopoietic develop-ment and the transformation into (pre-)leukemic states. In doing so, we observed a disruption in early myelomonocytic development. Accordingly, we identified gene profiles that were consistent with primary MLL-AF9 AML and uncovered high-confidence MLL-AF9-associated core genes that are faithfully represented in primary MLL-AF9 AML, including known and presently unknown factors. Using single-cell RNA-sequencing, we identified an increase of CD34 expressing early hematopoietic progenitor-like cell states as well as granulocyte-monocyte progenitor-like cells upon MLL-AF9 activation. Our system allows for careful chemically controlled and stepwise in vitro hiPSC-derived differentiation under serum-free and feeder-free conditions. For a disease that cur-rently lacks effective precision medicine, our system provides a novel entry-point into exploring po-tential novel targets for personalized therapeutic strategies.

2023-05-03 | GSE217014 | GEO

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