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Chronic IL-15 stimulation and impaired mTOR signaling and metabolism in natural killer cells during acute myeloid leukemia

ABSTRACT: Chronic IL-15 stimulation and impaired mTOR signaling and metabolism in natural killer cells during acute myeloid leukemia

PROVIDER: PRJNA748074 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15194200.fastq.gz	Fastqsanger.gz
	SRR15194195.fastq.gz	Fastqsanger.gz
	SRR15194196.fastq.gz	Fastqsanger.gz
	SRR15194197.fastq.gz	Fastqsanger.gz
	SRR15194198.fastq.gz	Fastqsanger.gz

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Chronic IL-15 Stimulation and Impaired mTOR Signaling and Metabolism in Natural Killer Cells During Acute Myeloid Leukemia.

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Chronic IL-15 stimulation and impaired mTOR signaling and metabolism in natural killer cells during acute myeloid leukemia

Project description:We report the application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells. By obtaining over four billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of mouse embryonic stem cells, neural progenitor cells and embryonic fibroblasts. We find that lysine 4 and lysine 27 trimethylation effectively discriminates genes that are expressed, poised for expression, or stably repressed, and therefore reflect cell state and lineage potential. Lysine 36 trimethylation marks primary coding and non-coding transcripts, facilitating gene annotation. Trimethylation of lysine 9 and lysine 20 is detected at satellite, telomeric and active long-terminal repeats, and can spread into proximal unique sequences. Lysine 4 and lysine 9 trimethylation marks imprinting control regions. Finally, we show that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms. This study provides a framework for the application of comprehensive chromatin profiling towards characterization of diverse mammalian cell populations.

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Project description:Natural killer (NK) cells have shown potential for allogeneic cell-based cancer immunotherapies. For development of economical off-the-shelf allogeneic therapies, maximal expansion of the NK cells from each donor must be achieved while maintaining efficacy and uniformity of the cell product. The most robust expansion method utilizes weekly stimulation with engineered feeder cells derived from the K562 cell line. However, the effects of repeated stimulation on NK cell growth, metabolism, and function are not well understood. In this study, we demonstrated a distinct shift in growth kinetics and metabolism around week 3-4 of repeated K562 feeder cell stimulation, followed by a change in cytokine secretion and killing ability. While Seahorse metabolic flux assays and transcriptomics suggested a transition from glycolytic metabolism to oxidative metabolism after the first week of stimulation, the shift in growth kinetics generally correlated to reduced metabolic activity. Collectively, these results indicate that serial stimulation sustains large-fold NK cell expansion that can be exploited for NK cell therapy; however, this expansion has important impacts on NK cell growth, metabolism, and function. Careful characterization is critical when developing large-scale biomanufacturing processes that ensure clinical efficacy of the final cellular product.

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Coulibaly2019 - Interleukin-15 Signaling in HIF-1a Regulation in Natural Killer Cells

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