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Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma

ABSTRACT: Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma

PROVIDER: PRJNA510095 | ENA |

REPOSITORIES: ENA

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Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma [microarray]

Project description:Drugs that modify the epigenome are powerful tools for treating cancer, but these drugs often have pleiotropic effects, and identifying patients who will benefit from them remains a major clinical challenge. Here we show that medulloblastomas driven by the transcription factor Gfi1 are exquisitely dependent on the enzyme lysine demethylase 1 (Kdm1a/Lsd1). We demonstrate that Lsd1 physically associates with Gfi1, and that these proteins cooperate to inhibit genes involved in neuronal commitment and differentiation. We also show that Lsd1 is essential for Gfi1-mediated transformation: Gfi1 proteins that cannot recruit Lsd1 are unable to drive tumorigenesis and genetic ablation of Lsd1 markedly impairs tumor growth in vivo. Finally, pharmacological inhibitors of Lsd1 potently inhibit growth of Gfi1-driven tumors. These studies provide important insight into the mechanisms by which Gfi1 contributes to tumorigenesis, and identify Lsd1 inhibitors as promising therapeutic agents for Gfi1-driven medulloblastoma.

2018-12-07 | GSE123409 | GEO

Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma [ChIP-seq]

2018-12-15 | GSE123870 | GEO

Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma [microarray]

Project description:Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma [microarray]

| PRJNA508643 | ENA

Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma [ChIP-seq]

Project description:Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma [ChIP-seq]

| PRJNA510098 | ENA

Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma.

Project description: Not available

| S-EPMC6338772 | biostudies-literature

HMG20B stabilizes interaction of LSD1 with GFI1 on chromatin to confer 1 transcription repression and leukemia cell differentiation block

Project description:Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukaemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we made use of mass spectrometry approaches. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is colocated on chromatin genome-wide with GFI1 and LSD1; the strongest HMG20B binding colocates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukaemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing the interaction on chromatin of LSD1 with GFI1. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukaemia cell differentiation block.

2023-03-11 | PXD030581 | Pride

Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-12-15 | GSE123871 | GEO

Inhibitors of LSD1 target demethylase-independent activity to induce differentiation in acute myeloid leukemia [anti-LSD1, MYB, and GFI1 ChIP-Seq]

Project description:To identify genomic binding regions, THP1 AML cells were subjected to ChIP sequencing (ChIPseq) using anti-LSD1, MYB or GFI1 antibodies.

2018-03-27 | GSE90769 | GEO

HMG20B stabilizes interaction of LSD1 with GFI1 on chromatin to confer transcription repression and leukemia cell differentiation block [RNA-seq]

2022-10-06 | GSE192974 | GEO

HMG20B stabilizes interaction of LSD1 with GFI1 on chromatin to confer transcription repression and leukemia cell differentiation block [ChIP-seq II]

2022-10-06 | GSE192973 | GEO