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Loss of the metabolic sensor, PPARA, overcomes differentiation blockade and immune suppression in AML

ABSTRACT: Loss of the metabolic sensor, PPARA, overcomes differentiation blockade and immune suppression in AML

PROVIDER: PRJNA667062 | ENA |

REPOSITORIES: ENA

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Loss of the metabolic sensor, PPARA, overcomes differentiation blockade and immune suppression in AML

Project description:The hematopoietic system balances self-renewal and differentiation in response to various environmental cues. The nuclear hormone receptor superfamily consists of ligand-activated transcription factors that allow cells to integrate external stimuli with cellular programs regulating differentiation, metabolism, proliferation and survival. We and others have shown that members of this family play central roles in normal, stress and malignant hematopoiesis. Here, we report that expression of PPAR-alpha is elevated in patients with high risk subtypes of acute myeloid leukemia (AML). On this basis, we hypothesized that genetic disruption of the alpha isoform of PPAR would selectively impair AML maintenance while sparing normal hematopoietic stem progenitor cells. Indeed, Ppara null MLL-AF9 leukemia displayed a relief of its differentiation blockade, a hallmark of acute leukemia. This restored differentiation was accompanied by gene expression patterns indicative of altered metabolic pathways and immune signaling. By contrast, steady-state and stress myelopoiesis were largely unaffected by the loss of Ppara with the exception of a mild increase in differentiated myeloid cells. Notably, a significant survival advantage was observed in Ppara deleted AML as compared to controls. In contrast, transplantation into Rag2-/- recipients substantially reduced this survival advantage, demonstrating dependence on the adaptive arm of the immune system. These results suggest possible therapeutic implications for immune modulation through pharmacologic targeting of PPARA signaling. Taken together, our in vivo studies of Ppara in MLL-AF9 AML are consistent with a model in which concomitant regulation of cell-intrinsic programs and modulation of interactions with the leukemic immune microenvironment by PPARA promotes leukemia maintenance.

2020-10-03 | GSE158938 | GEO

Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade

Project description:Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade

| PRJNA797384 | ENA

Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade

Project description:Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade

| PRJNA797777 | ENA

Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade II

Project description:Disruption of dNTPs Homeostasis by Ribonucleotide Reductase Hyperactivation Overcomes AML Differentiation Blockade II

| PRJNA798053 | ENA

Genome-wide profiling of PPARA in PPARA agonist-treated mouse livers [ChIP-seq]

Project description:To clarify mouse PPARA autoinduction and hepatocyte proliferation signaling pathways, genome-wide distribution of PPARA in the liver of PPARA agonist-treated mice compared to Vehicle was analyzed.

2022-04-05 | GSE154276 | GEO

BMP receptor blockade overcomes extrinsic inhibition of remyelination and restores neurovascular homeostasis

Project description:BMP receptor blockade overcomes extrinsic inhibition of remyelination and restores neurovascular homeostasis

| PRJNA701573 | ENA

Expression profiling in liver of wild type and Ppara-null mice treated with PPARA agonists [RNA-seq]

Project description:To clarify the mechanism underlying the proliferation of hepatocytes induced by PPARA agonists, expression profiling in liver of wild type and Ppara-null mice treated with PPARA agonist was investigated.

2022-04-05 | GSE154275 | GEO

Global hepatic gene expression data from PPARa liver KO, PPARa liver WT, PPARaKO and WT male mice treated or not with Fenofibrate

Project description:Fenofibrate is a specific agonist of the nuclear receptor PPARa. To identify the gene expression under the strict dependence of hepatic PPARa activity, we generated a new mouse strain of PPARa-specific deletion in hepatocyte (albumin-Cre+/- Pparaflox/flox or LKO) and we compared them to total Ppara KO (KO), wild-type (WT) and liver WT (albumin-Cre-/- Pparaflox/flox or LWT) mice. We used microarrays to detail the global programme of gene expression in liver of Ppara LKO, LWT, Ppara KO and WT male mice.

2016-02-20 | GSE73298 | GEO

Disruption of dNTP homeostasis by ribonucleotide reductase hyperactivation overcomes AML differentiation blockade.

Project description:Differentiation blockade is a hallmark of acute myeloid leukemia (AML). A strategy to overcome such a blockade is a promising approach against the disease. The lack of understanding of the underlying mechanisms hampers development of such strategies. Dysregulated ribonucleotide reductase (RNR) is considered a druggable target in proliferative cancers susceptible to deoxynucleoside triphosphate (dNTP) depletion. Herein, we report an unanticipated discovery that hyperactivating RNR enables differentiation and decreases leukemia cell growth. We integrate pharmacogenomics and metabolomics analyses to identify that pharmacologically (eg, nelarabine) or genetically upregulating RNR subunit M2 (RRM2) creates a dNTP pool imbalance and overcomes differentiation arrest. Moreover, R-loop-mediated DNA replication stress signaling is responsible for RRM2 activation by nelarabine treatment. Further aggravating dNTP imbalance by depleting the dNTP hydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) enhances ablation of leukemia stem cells by RRM2 hyperactivation. Mechanistically, excessive activation of extracellular signal-regulated kinase (ERK) signaling downstream of the imbalance contributes to cellular outcomes of RNR hyperactivation. A CRISPR screen identifies a synthetic lethal interaction between loss of DUSP6, an ERK-negative regulator, and nelarabine treatment. These data demonstrate that dNTP homeostasis governs leukemia maintenance, and a combination of DUSP inhibition and nelarabine represents a therapeutic strategy.

| S-EPMC9247363 | biostudies-literature

Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation

Project description:Peroxisome proliferator-activated receptor α (PPARA) is a key mediator of lipid metabolism and inflammation. Activation of PPARA in rodents causes hepatocyte proliferation, but the underlying mechanism is poorly understood. This study focused on genes repressed by PPARA and analyzed the mechanism by which PPARA promotes hepatocyte proliferation in mice. Activation of PPARA by agonist treatment was autoregulated, and induced expression of the epigenetic regulator UHRF1 via activation of the newly described PPARA target gene E2f8, that in turn regulates Uhrf1. UHRF1 strongly repressed expression of CDH1 via methylation of the Cdh1 promoter marked with H3K9me3. Repression of CDH1 by PPARA activation was reversed by PPARA deficiency or knockdown of E2F8 or UHRF1. Furthermore, forced expression of CDH1 inhibited expression of the Wnt signaling target genes such as Myc after PPARA activation, and suppressed hepatocyte hyperproliferation. These results demonstrate that the PPARA-E2F8-UHRF1-CDH1 axis causes epigenetic regulation of hepatocyte proliferation. This SuperSeries is composed of the SubSeries listed below.

2022-04-05 | GSE154277 | GEO

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