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Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia [ATAC-Seq]

ABSTRACT: A hallmark of acute myeloid leukemia (AML) is the inability of self-renewing malignant cells to mature into a non-dividing terminally differentiated state. To better understand how chromatin factors such as LSD1 interact with metabolic pathways to support the differentiation blockade, we screened a small molecule library to identify druggable substrates that promote myeloid maturation. We found that differentiation caused by LSD1 inhibition is enhanced by combinatorial perturbation of purine nucleotide salvage and de novo lipogenesis pathways. We used ATAC-seq to determine whether the drug combination induces chromatin changes.

ORGANISM(S): Mus musculus

PROVIDER: GSE162397 | GEO | 2020/12/04

REPOSITORIES: GEO

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Project description:The ability of Leishmania to survive in their insect or mammalian host is dependent upon an ability to sense and adapt to changes in the microenvironment. However, little is known about the molecular mechanisms underlying the parasite response to environmental changes, such as nutrient availability. To elucidate nutrient stress response pathways in Leishmania donovani, we have used purine starvation as the paradigm. The salvage of purines from the host milieu is obligatory for parasite replication; nevertheless, purine-starved parasites can persist in culture without supplementary purine for over 3 months, indicating that the response to purine starvation is robust and engenders parasite survival under conditions of extreme scarcity. To understand metabolic reprogramming during purine starvation we have employed global approaches. Whole proteome comparisons between purine-starved and purine-replete parasites over a 6-48 h span have revealed a temporal and coordinated response to purine starvation. Purine transporters and enzymes involved in acquisition at the cell surface are upregulated within a few hours of purine removal from the media, while other key purine salvage components are upregulated later in the time-course and more modestly.Â After 48 h, the proteome of purine-starved parasites is extensively remodeled and adaptations to purine stress appear tailored to deal with both purine deprivation and general stress. To probe the molecular mechanisms affecting proteome remodeling in response to purine starvation, comparative RNA-seq analyses, qRT-PCR, and luciferase reporter assays were performed on purine-starved versus purine-replete parasites.Â While the regulation of a minority of proteins tracked with changes at the mRNA level, for many regulated proteins it appears that proteome remodeling during purine stress occurs primarily via translational and post-translational mechanisms. One mRNA sample from each of Purine-Starved and Purine-Replete cells were analyzed using SL RNA-Seq methodology

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Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia [ATAC-Seq]

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