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Evi1 upregulates Fbp1 and supports progression of acute myeloid leukemia through pentose phosphate pathway activation.

ABSTRACT: Evi1 is a transcription factor essential for the development as well as progression of acute myeloid leukemia (AML) and high Evi1 AML is associated with extremely poor clinical outcome. Since targeting metabolic vulnerability is the emerging therapeutic strategy of cancer, we herein investigated a novel therapeutic target of Evi1 by analyzing transcriptomic, epigenetic, and metabolomic profiling of mouse high Evi1 leukemia cells. We revealed that Evi1 overexpression and Evi1-driven leukemic transformation upregulate transcription of gluconeogenesis enzyme Fbp1 and other pentose phosphate enzymes with interaction between Evi1 and the enhancer region of these genes. Metabolome analysis using Evi1-overexpressing leukemia cells uncovered pentose phosphate pathway upregulation by Evi1 overexpression. Suppression of Fbp1 as well as pentose phosphate pathway enzymes by shRNA-mediated knockdown selectively decreased Evi1-driven leukemogenesis in vitro. Moreover, pharmacological or shRNA-mediated Fbp1 inhibition in secondarily transplanted Evi1-overexpressing leukemia mouse significantly decreased leukemia cell burden. Collectively, targeting FBP1 is a promising therapeutic strategy of high Evi1 AML.

SUBMITTER: Mizuno H

PROVIDER: S-EPMC8486204 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Elevated pentose phosphate pathway flux supports appendage regeneration.

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PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cell through regulation of the pentose phosphate pathway

Project description:Leukemia stem cells (LSCs) are responsible for the initiation, progression, and recurrence of leukemia. Targeting LSCs is thought as an effective way to cure leukemia, for which it is pivotal to identify novel therapeutic targets. The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is frequently activated in acute myeloid leukemia (AML) and strongly contributes to survival and proliferation of leukemia cells. Herein, we revealed that the p110γ isoform of PI3K was highly expressed in both mouse and human LSCs. Leukemogenesis was drastically delayed upon Pik3cg deletion during serial transplantations in murine acute myeloid leukemia models. Knockout of Pik3cg resulted in a remarkably impaired self-renewal, enhanced differentiation, and 32-fold reduced number of mouse acute myeloid LSCs. Interestingly, Pik3cg deficiency did not alter the functions of mouse hematopoietic stem cells. Mechanistically, PIK3CG/AKT/NRF2/PGD signaling axis controlled the pentose phosphate pathway to regulate redox metabolism and support nucleotide synthesis to maintain LSC fates. PIK3CG knockdown also led to a significant extended survival of recipients transplanted with human AML cells. Pharmaceutical inhibition of PIK3CG could efficiently restrain the progression of AML. PIK3CG may serve as a potential therapeutic target for the elimination of LSCs without influencing normal hematopoiesis.

2024-02-02 | GSE224607 | GEO

Global Identification of EVI1 Target Genes in Acute Myeloid Leukemia.

Project description:The ecotropic virus integration site 1 (EVI1) transcription factor is associated with human myeloid malignancy of poor prognosis and is overexpressed in 8-10% of adult AML and strikingly up to 27% of pediatric MLL-rearranged leukemias. For the first time, we report comprehensive genomewide EVI1 binding and whole transcriptome gene deregulation in leukemic cells using a combination of ChIP-Seq and RNA-Seq expression profiling. We found disruption of terminal myeloid differentiation and cell cycle regulation to be prominent in EVI-induced leukemogenesis. Specifically, we identified EVI1 directly binds to and downregulates the master myeloid differentiation gene Cebpe and several of its downstream gene targets critical for terminal myeloid differentiation. We also found EVI1 binds to and downregulates Serpinb2 as well as numerous genes involved in the Jak-Stat signaling pathway. Finally, we identified decreased expression of several ATP-dependent P2X purinoreceptors genes involved in apoptosis mechanisms. These findings provide a foundation for future study of potential therapeutic gene targets for EVI1-induced leukemia.

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The Pentose Phosphate Pathway Regulates the Circadian Clock.

Project description:The circadian clock is a ubiquitous timekeeping system that organizes the behavior and physiology of organisms over the day and night. Current models rely on transcriptional networks that coordinate circadian gene expression of thousands of transcripts. However, recent studies have uncovered phylogenetically conserved redox rhythms that can occur independently of transcriptional cycles. Here we identify the pentose phosphate pathway (PPP), a critical source of the redox cofactor NADPH, as an important regulator of redox and transcriptional oscillations. Our results show that genetic and pharmacological inhibition of the PPP prolongs the period of circadian rhythms in human cells, mouse tissues, and fruit flies. These metabolic manipulations also cause a remodeling of circadian gene expression programs that involves the circadian transcription factors BMAL1 and CLOCK, and the redox-sensitive transcription factor NRF2. Thus, the PPP regulates circadian rhythms via NADPH metabolism, suggesting a pivotal role for NADPH availability in circadian timekeeping.

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Project description:Two hallmarks for cancer cells are the accelerated cell cycle progression as well as the altered metabolism, however, how these changes are coordinated to optimize the growth advantage for cancer cells are still poorly understood. Here we identify that Polo-like kinase 1 (Plk1), a key regulator for cell mitosis, plays a critical role for biosynthesis in cancer cells through activating pentose phosphate pathway (PPP). We find that Plk1 interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase (G6PD). By activating G6PD through promoting the formation of its active dimer, Plk1 increases PPP flux and directs glucose to the synthesis of macromolecules. Importantly, we further demonstrate that Plk1-mediated activation of G6PD is critical for its role to promote cell cycle progression and cancer cell growth. Collectively, these findings establish a critical role for Plk1 in regulating biosynthesis in cancer cells, exemplifying how cell cycle progression and metabolic reprogramming are coordinated for cancer progression.

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2021-07-27 | PXD023550 | Pride

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