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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE123409 | GEO | 2018/12/07

REPOSITORIES: GEO

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

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. ChIP-seq data generated for n=2 MG (Myc/Gfi1) murine medulloblastomas. ChIP was independently performed for Gfi1 and Lsd1 on the same chromatin extracts.

2018-12-15 | GSE123870 | GEO

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.

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Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells [RNA-seq]

Project description:To determine the impact of inhibition of KDM1A/LSD1 through genetic manipulation by CRISPR/Cas9 or inducible shRNA or following treatment with irreversible LSD1 inhibitor INCB059872 on global transcriptomic profile in AML and post-MPN sAML cells. To determine the impact of GFI1 knockdown on global transcriptomic profile in AML cells.

2021-05-26 | GSE160303 | GEO

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

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

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

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Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells [ChIP-seq]

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2021-05-26 | GSE160318 | GEO

Targeted inhibition of GFI1/KDM1A combined with BET inhibitor augments lethal activity against AML including post-MPN sAML cells [ATAC-seq]

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Differential gene expression profiling by LSD1 inhibition using novel LSD1 inhibitors (NCD25 and NCD38)

Project description:LSD1 is a demethylase of histone modification H3k4me1 and H3K4me2. We have developed novel LSD1 inhibitors (NCD25 and NCD38) and found that they are effective to myelodysplastic syndromes and leukemia cells. To understand what mechanisms are affected by these compounds, we employed gene expression profiling analyses. Gene expression profiling data were obtained from HEL, MDS-L, or CMK11-5 cells treated with DMSO (control), NCD25, or NCD38 and compared each other. Expression of eleven transcriptional factors (GFI1, CEBPA, SPI1, MNDA, TAL1, GATA1, NFE2, RXRA, HOXA9, GATA2, and PBX1) was reconfirmed by q-PCR with the same samples. Gene expression of leukemia cells was measured after 48 hours incubation with or without LSD1 inhibitors. Five independent experiments were performed using 3 cell lines (HEL, MDS-L and CMK11-5) and 2 drugs (NCD38 and NCD25).

2015-04-29 | E-GEOD-68348 | biostudies-arrayexpress

Inactivation of Ezh2 upregulates Gfi1 and drives aggressive Myc-driven Group 3 medulloblastoma [ChIP-Seq]

Project description:The most aggressive of four medulloblastoma (MB) subgroups are cMYC-driven Group 3 (G3) tumors, some of which overexpress EZH2, the histone H3K27 trimethylase of polycomb repressive complex-2. Yet, engineered deletions of Ezh2 in G3 MBs by gene editing nucleases accelerated tumorigenesis, whereas Ezh2 re-expression reversed attendant histone modifications and slowed tumor progression. Candidate oncogenic drivers upregulated following Ezh2 deletion included Gfi1, a proto-oncogene frequently activated in human G3 MBs. Gfi1 disruption antagonized the tumor promoting effects of Ezh2 loss; conversely, Gfi1 overexpression collaborated with Myc to bypass effects of Trp53 inactivation in primary cerebellar neuronal progenitors thereby driving MB progression. Although negative epigenetic regulation of Gfi1 by Ezh2 may restrain MB development, Gfi1 activation can bypass these effects.

2017-03-01 | GSE84761 | GEO

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