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SIRT1 regulates enhanced mitochondrial respiration and leukemogenicity in CML stem cells

ABSTRACT: SIRT1 regulates enhanced mitochondrial respiration and leukemogenicity in CML stem cells

PROVIDER: PRJNA530246 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8833070_1.fastq.gz	Fastqsanger.gz
	SRR8833070_2.fastq.gz	Fastqsanger.gz
	SRR8833071_1.fastq.gz	Fastqsanger.gz
	SRR8833071_2.fastq.gz	Fastqsanger.gz
	SRR8833064_1.fastq.gz	Fastqsanger.gz

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SIRT1 regulates enhanced mitochondrial respiration and leukemogenicity in CML stem cells

Project description:Chronic myeloid leukemia (CML) results from hematopoietic stem cell transformation by the BCR-ABL tyrosine kinase. We have shown that the SIRT1 deacetylase is overexpressed in CML LSC, and may contribute to their maintenance. Here, using genetic deletion of SIRT1 in transgenic CML mice, we definitively demonstrate that SIRT1 is required for leukemia development, and reveal its critical role in mediating increased mitochondrial respiration in CML LSC.

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TNFα-induced alterations in stromal progenitors in CML BM result in enhanced LSC growth via CXCL1-CXCR2 signaling

Project description:Leukemia stem cells (LSC) are not eradicated in chronic myeloid leukemia (CML) patients responding to tyrosine kinase inhibitor treatment. Bone marrow (BM) mesenchymal niches play an essential role in hematopoietic stem cell (HSC) maintenance. Here, we examined leukemia-induced alterations in mesenchymal progenitor populations using a murine CML model. 6C3+ stroma-forming progenitors were increased in CML BM, and demonstrated enhanced LSC but reduced HSC support compared to their normal counterparts. CML 6C3 cells showed enhanced TNFa-related gene signatures, and upregulated CXCL1 expression. TNFα signaling contributed to expansion and increased CXCL1 expression by 6C3 cells in CML BM. The CXCL1 receptor CXCR2 was upregulated in in LSC, and CXCR2 inhibition significantly reduced LSC growth both in vitro and in vivo. In conclusion, TNFα-induced alterations in stromal progenitors in CML BM result in enhanced CML LSC growth via CXCL1-CXCR2 signaling. Targeting this axis represents a novel therapeutic strategy to inhibit BM niche-protected LSC.

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Releasing the mitochondrial respiration brake MCJ/DnaJC15 enhances CD8 CAR-T cell therapy efficacy

Project description:Metabolism of chimeric antigen receptor (CAR) T cells is emerging as an important area to improve CAR-T cell therapy in cancer treatment. Mitochondrial respiration is essential for survival and function of CAR-T cells, but developing strategies to specifically enhance mitochondrial respiration has been challenging. Here we identify MCJ/DnaJC15, an endogenous negative regulator of mitochondrial Complex I, as a metabolic target to enhance mitochondrial respiration in CD8 CAR-T cells. Loss of MCJ in CD8 CAR-T cells increases their in vitro and in vivo efficacy against mouse B cell leukemias. MCJ deficiency in TCR- specific CD8 cells also increases their efficacy against solid tumors in vivo. Furthermore, we reveal that human CD8 cells express MCJ and that silencing MCJ expression increases mitochondrial metabolism and anti-tumor activity of human CAR-T cells. Thus, we demonstrate the unique therapeutic potential of targeting MCJ to enhance the metabolism and efficacy of adoptive T cell therapies.

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Transcriptomic analysis by array of reactivation of dihydroorotate dehydrogenase by respiration restores tumor growth of mitochondrial DNA-depleted cancer cells.

Project description:Tumor cells without mitochondrial DNA (mtDNA) reconstitute oxidative phosphorylation (OXPHOS) by acquiring host mitochondria from stromal cells, but the reasons why functional respiration is crucial for tumorigenesis remain unclear. To address this issue, we used time-resolved analysis of the initial stages of tumor formation by cells devoid of mtDNA and genetic manipulations of components of OXPHOS. We show that pyrimidine biosynthesis, supported by respiration-linked dihydroorotate dehydrogenase (DHODH), is strictly required to overcome cell cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis.

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MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

Project description:MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

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Cytosolic Ribosomal Protein Haploinsufficiency affects Mitochondrial Morphology and Respiration

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Project description:Metabolic reprogramming is an active regulator of stem cell fate choices, and successful stem cell differentiation in different compartments requires the induction of oxidative phosphorylation. However, the mechanisms that promote mitochondrial respiration during stem cell differentiation are poorly understood. Here we demonstrate that Stat3 promotes muscle stem cell myogenic lineage progression by stimulating mitochondrial respiration. We identify Fam3a, a cytokine-like protein, as a major Stat3 downstream effector in muscle stem cells. We demonstrate that Fam3a is required for muscle stem cell commitment and skeletal muscle development. We show that myogenic cells secrete Fam3a, and exposure of Stat3-ablated muscle stem cells to recombinant Fam3a in vitro and in vivo rescues their defects in mitochondrial respiration and myogenic commitment. Together, these findings indicate that Fam3a is a Stat3-regulated secreted factor that promotes muscle stem cell oxidative metabolism and differentiation, and suggests that Fam3a is a potential tool to modulate cell fate choices.

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Project description:Recent evidences have linked indole-3-acetic acid (I3A), a gut microbiota-derived metabolite from dietary tryptophan, with the resistance to liver diseases. However, data supporting I3A-mediated protection against nonalcoholic fatty liver disease (NAFLD) remain incomprehensive. In this study, we verified that I3A definitely alleviates dietary-induced metabolic impairments, particularly glucose dysmetabolism and liver steatosis. Importantly, we expand the understanding of I3A further to enhancing mitochondrial respiration complex (MRC) capacity by RNA-seq. We found that I3A restored the deficiency of MRC capacity in palmitic acid (PA)-induced HepG2 in vitro. These changes were associated with complex I and III expression and their activities. In addition, pre-treatment of I3A guard against the deficiency of not only the MRC capacity but also ATP production due to the advanced protection effect on the expression and activity of complex V. In conclusion, our findings uncover that I3A increased expression and activity of hepatic oxidative phosphorylation subunits, contributing to mitochondrial respiration improvement in NAFLD mice.

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Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis

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