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PU.1 and MYC transcriptional network defines a synergist drug response to combined KIT and LSD1 inhibition in acute myeloid leukemia

ABSTRACT: PU.1 and MYC transcriptional network defines a synergist drug response to combined KIT and LSD1 inhibition in acute myeloid leukemia

PROVIDER: PRJNA754794 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15462300_1.fastq.gz	Fastqsanger.gz
	SRR15462300_2.fastq.gz	Fastqsanger.gz
	SRR15462400_1.fastq.gz	Fastqsanger.gz
	SRR15462400_2.fastq.gz	Fastqsanger.gz
	SRR15462301_1.fastq.gz	Fastqsanger.gz

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PU.1 and MYC transcriptional network defines a synergist drug response to combined KIT and LSD1 inhibition in acute myeloid leukemia

Project description:KIT mutant acute myeloid leukemia (AML) confers a worse prognosis for patients in a subtype of AML that has an otherwise favorable outcome. Here, we demonstrate that lysine specific demethylase 1 (LSD1) inhibition potentiates cytotoxic effect of KIT inhibition in KIT mutant AML. We identified loss of PU.1 binding to be a key feature of LSD1 inhibition, contributing to a decrease in MYC enhancer and promoter activation. This loss of MYC enhancer/promoter activation results in decreased MYC expression and binding at proliferation associated promoters decreasing cell cycle progression. Our results nominate PI3K/AKT pathway inactivation as a key feature of KIT and LSD1 inhibition ultimately leading to decreased MYC and blocking LSD1 from activating its targets. Our findings support a mechanistic model for synergy between dual KIT and LSD1 inhibition and suggest this combination should be investigated in a clinical setting.

2022-05-29 | GSE182150 | GEO

PU.1 and MYC transcriptional network defines synergistic drug responses to KIT and LSD1 inhibition in acute myeloid leukemia.

Project description:Responses to kinase-inhibitor therapy in AML are frequently short-lived due to the rapid development of resistance, limiting the clinical efficacy. Combination therapy may improve initial therapeutic responses by targeting pathways used by leukemia cells to escape monotherapy. Here we report that combined inhibition of KIT and lysine-specific demethylase 1 (LSD1) produces synergistic cell death in KIT-mutant AML cell lines and primary patient samples. This drug combination evicts both MYC and PU.1 from chromatin driving cell cycle exit. Using a live cell biosensor for AKT activity, we identify early adaptive changes in kinase signaling following KIT inhibition that are reversed with the addition of LSD1 inhibitor via modulation of the GSK3a/b axis. Multi-omic analyses, including scRNA-seq, ATAC-seq and CUT&Tag, confirm these mechanisms in primary KIT-mutant AML. Collectively, this work provides rational for a clinical trial to assess the efficacy of KIT and LSD1 inhibition in patients with KIT-mutant AML.

| S-EPMC9256806 | biostudies-literature

LSD1 inhibition exerts its anti-leukemic effect by recommissioning PU.1- and C/EBPα-dependent enhancers in AML [ChIP-seq]

Project description:Epigenetic regulators are recurrently mutated and aberrantly expressed in acute myeloid leukemia (AML). Targeted therapies designed to inhibit these chromatin-modifying enzymes, such as the histone demethylase lysine specific demethylase 1 (LSD1) and the histone methyltransferase DOT1L, have been developed as novel treatment modalities for these often refractory diseases. A common feature of many of these targeted agents is their ability to induce myeloid differentiation, suggesting that multiple paths toward a myeloid gene expression program can be engaged to relieve the differentiation blockade that is uniformly seen in AML. We performed a comparative assessment of chromatin dynamics during the treatment of MLL-AF9-driven murine leukemias and MLL-rearranged patient-derived xenografts using two distinct but effective differentiation-inducing targeted epigenetic therapies, the LSD1 inhibitor GSK-LSD1 and the DOT1L inhibitor EPZ4777. Intriguingly, GSK-LSD1 treatment caused global gains in chromatin accessibility, whereas treatment with EPZ4777 caused global losses in accessibility. We captured PU.1 and C/EBPα motif signatures at LSD1 inhibitor-induced dynamic sites and ChIP-seq revealed co-occupancy of these myeloid transcription factors at these sites. Functionally, we confirmed that diminished expression of PU.1 or genetic deletion of C/EBPα in MLL-AF9 cells generates resistance of these leukemias to LSD1 inhibition. These findings reveal that pharmacologic inhibition of LSD1 represents a unique path to overcome the differentiation block in AML for therapeutic benefit.

2018-06-25 | GSE100758 | GEO

LSD1 inhibition exerts its anti-leukemic effect by recommissioning PU.1- and C/EBPα-dependent enhancers in AML [ATAC-seq]

2018-06-25 | GSE100757 | GEO

LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML

Project description:Lsd1KO and ATRA treatment in Hoxa9/Meis1- and MN1-transformed myeloid progenitor cells LSD1 has emerged as a promising epigenetic target in the treatment of acute myeloid leukemia (AML). Inhibition of LSD1 has been shown to induce differentiation and facilitate the responsiveness of AML cells to all-trans retinoic acid. We used two murine AML models based on retroviral overexpression of Hoxa9/Meis1 (H9M) or MN1 to study the effect of Lsd1 knockout in AML. The conditional knockout of Lsd1 resulted in differentiation with both granulocytic and monocytic features in H9M-induced AML cells and enhanced their responsiveness towards ATRA treatment, which was not seen in MN1-driven AML. It also extended the survival of mice with H9M-driven AML. To identify molecular changes associated with the loss of Lsd1, we performed whole transcriptome analysis by RNA sequencing of H9M and MN1 Lsd1 fl/fl (Ctrl) and Lsd1cKO cells with or without ATRA treatment. The experiment was done in triplicates. The conditional knockout led to a broad increase in the expression of multiple genes regulated by the important myeloid transcription factors GFI1 and PU.1. These include the transcription factors GFI1B and IRF8, which may be relevant for the observed differentiation response.

2019-01-08 | GSE110178 | GEO

PU.1

Project description:PU.1

| PRJNA344317 | ENA

Wild - type and PU.1 Q202L mutant mice ST - HSC (lin- c-kit+ Sca-1+ CD150- CD48-) and GMP (lin- c-kit+ Sca-1- CD16/32hi CD34+)

Project description:Identification of differentially regulated genes in the PU.1 Q202L point mutant that disrupts association with c-Jun. The goal was to identify PU.1 target genes that depend on the co-activation of PU.1 by c-Jun. Mice have normal ST-HSC but lack normal GMP, so a population of GMP-like cells was used in the mutant.

2016-03-07 | GSE27873 | GEO

Gene expression data of Lsd1fl/fl and Lsd1fl/fl Mx1Cre CD150+ CD48- lin- c-Kit+ Sca-1+ LT-HSCs

Project description:We discovered that mice that lack Lsd1 in hematopoietic cells were exhibited increased frequencies of CD150+ CD48- lin- c-Kit+ Sca-1+ LT-HSCs, but completely lacked the lin- c-Kit+ Sca-1- myeloid progenitor compartment. To determine the genes altered by Lsd1-loss, CD150+ CD48- lin- c-Kit+ Sca-1+ LT-HSCs from Lsd1fl/fl and Lsd1fl/fl Mx1Cre mice were FACS-purified to be analyzed by gene expression profiling.

2013-06-25 | GSE40284 | GEO

LSD1 complexes - Lsd1 Ablation Triggers Metabolic Reprogramming of Brown Adipose Tissue

Project description:Lsd1 ablation triggers metabolic reprogramming of brown adipose tissue. Lsd1 protein complexes were purified from mouse adipose tissue and analyzed by label-free LC-MS/MS. Mice were kept under different conditions prior complex isolation.

2017-01-03 | PXD004745 | Pride

The miR-155/PU.1 axis acts on Pax5 to enable efficient terminal B cell differentiation [ChIP-Seq]

Project description:miR-155 inhibits PU.1 expression, leading to the initiation of the initiation of plasma cell differentiation pathway. Additional PU.1 targets include a network of genes whose products are involved in adhesion, with direct links to B:T interactions. Sequencing analysis of PU.1 binding in B cells using Illumina ChIP-seq sample prep kit and Illumina platform. Cells were from ex-vivo LPS and IL-4 activated (96h) splenic B cells from wild type, PU.1[155-/155-] and miR-155[-/-] mice.

2014-09-26 | E-GEOD-61424 | biostudies-arrayexpress

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