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Transcriptomic analysis of AML bone marrow biopsies in a Phase II trial of cytarabine and mitoxantrone with devimistat

ABSTRACT: Devimistat is a novel TCA cycle inhibitor. A previously completed phase I study of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia (AML) showed promising response rates. A single arm phase II study (NCT02484391) of AML patients to assess the feasibility of maintenance devimistat, response, survival and safety is now complete. A dose response was observed in older patients, but not younger patients. RNAseq analysis of pre-treatment bone marrow biopsies revealed an age-related decline in mitochondrial gene sets. Devimistat impairs ATP synthesis, and there is a direct correlation between mitochondrial membrane potential and chemotherapy sensitization. Devimistat induces mitochondrial reactive oxygen species and turnover consistent with mitophagy. Pharmacological or genetic inhibition of mitochondrial fission or autophagy sensitizes cells to devimistat. These data support a model where devimistat may benefit older patients as a consequence of age related decline in mitochondrial quality and autophagy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE195933 | GEO | 2022/02/08

REPOSITORIES: GEO

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Mito-protective autophagy is impaired in erythroid cells of aged mtDNA-mutator mice

Project description:Somatic mitochondrial DNA (mtDNA) mutations contribute to the pathogenesis of age-related disorders, including myelodysplastic syndromes (MDS). The accumulation of mitochondria harboring mtDNA mutations in patients with these disorders suggests a failure of normal mitochondrial quality-control systems. The mtDNA-mutator mice acquire somatic mtDNA mutations via a targeted defect in the proofreading function of the mtDNA polymerase, PolgA, and develop macrocyticanemia similar to that of patients with MDS. We observed an unexpected defect in clearance of dysfunctional mitochondria at specific stages during erythroid maturation in hematopoietic cells from aged mtDNA-mutator mice. Mechanistically, aberrant activation of mechanistic target of rapamycin signaling and phosphorylation of uncoordinated 51-like kinase (ULK) 1 in mtDNA-mutator mice resulted in proteasome mediated degradation of ULK1 and inhibition of autophagy in erythroid cells. To directly evaluate the consequence of inhibiting autophagy on mitochondrial function in erythroid cells harboring mtDNA mutations in vivo, we deleted Atg7 from erythroid progenitors of wildtype and mtDNA-mutator mice. Genetic disruption of autophagy did not cause anemia in wild-type mice but accelerated the decline in mitochondrial respiration and development of macrocytic anemia in mtDNA-mutator mice. These findings highlight a pathological feedback loop that explains how dysfunctional mitochondria can escape autophagy-mediated degradation and propagate in cells predisposed to somatic mtDNA mutations, leading to disease. We used microarrays to identify expression profiles and pathways that are differentially activated or suppressed in Ter119+ bone marrow cells isolated from phlebotomized wildtype or Polg mutant mice

2015-04-21 | E-GEOD-57761 | biostudies-arrayexpress

Age-associated changes in human CD4+ T cells point to mitochondrial dysfunction consequent to impaired autophagy.

Project description:To gain understanding on the mechanisms that drive immunosenescence in humans, we examined CD4+ T cells obtained from younger (20-39 years-old) and older (70+ years-old) healthy participants of the Baltimore Longitudinal Study on Aging (BLSA). We found that mitochondrial proteins involved in the electron transport chain were overrepresented in cells from older participants, with prevalent dysregulation of oxidative phosphorylation and energy metabolism molecular pathways. Surprisingly, gene transcripts coding for mitochondrial proteins pertaining to oxidative phosphorylation and electron transport chain pathways were underrepresented in older individuals. Paralleling the observed decrease in gene expression, mitochondrial respiration was impaired in CD4+ T cells from older subjects. Though mitochondrial number in both naïve and memory cells visualized with electron microcopy was similar in older versus younger participants, there were a significantly higher number of autophagosomes, many of them containing undegraded mitochondria, in older individuals. The presence of mitochondria inside the accumulated autophagic compartments in CD4+ T cells from older individuals was confirmed by immunofluorescence. These findings suggest that older age is associated with persistence of dysfunctional mitochondria in CD4+ T lymphocytes caused by defective mitochondrial turnover by autophagy, which may trigger chronic inflammation and contribute to the impairment of immune defense in older persons.

2019-11-12 | GSE131407 | GEO

Ribosome profiling analysis of aging human skeletal muscle (Ribo-Seq)

Project description:With advancing age, human muscle loses strength and function, but the molecular causes of these losses are unknown. Skeletal muscle shows an age-dependent decline in the levels of different proteins, but whether such decline is associated with reduced translation has not been studied. To address this gap of knowledge, we used the technique of ribosome profiling to study translation in muscle from middle-aged and old individuals. Using ribosome occupancy as a measure of translation status, several mRNAs showed differential translation with age. Older age was associated with lower translation of myosin and titin isoforms and more broadly with the translation of proteins involved in oxidative phosphorylation encoded by the mitochondrial genome. Based on our findings, we propose that mitochondrial proteins are less translated in old skeletal muscle.

2021-03-08 | GSE152556 | GEO

Ribosome profiling analysis of aging human skeletal muscle (RNA-Seq)

2021-03-08 | GSE152554 | GEO

Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis

Project description:Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis

| PRJNA741923 | ENA

Age-associated changes in human CD4+ T cells point to mitochondrial dysfunction consequent to impaired autophagy

2019-11-27 | PXD016039 | Pride

Mito-protective autophagy is impaired in erythroid cells of aged mtDNA-mutator mice

Project description:Somatic mitochondrial DNA (mtDNA) mutations contribute to the pathogenesis of age-related disorders, including myelodysplastic syndromes (MDS). The accumulation of mitochondria harboring mtDNA mutations in patients with these disorders suggests a failure of normal mitochondrial quality-control systems. The mtDNA-mutator mice acquire somatic mtDNA mutations via a targeted defect in the proofreading function of the mtDNA polymerase, PolgA, and develop macrocytic anemia similar to that of patients with MDS. We observed an unexpected defect in clearance of dysfunctional mitochondria at specific stages during erythroid maturation in hematopoietic cells from aged mtDNA-mutator mice. Mechanistically, aberrant activation of mechanistic target of rapamycin signaling and phosphorylation of uncoordinated 51-like kinase (ULK) 1 in mtDNA-mutator mice resulted in proteasome mediated degradation of ULK1 and inhibition of autophagy in erythroid cells. To directly evaluate the consequence of inhibiting autophagy on mitochondrial function in erythroid cells harboring mtDNA mutations in vivo, we deleted Atg7 from erythroid progenitors of wildtype and mtDNA-mutator mice. Genetic disruption of autophagy did not cause anemia in wild-type mice but accelerated the decline in mitochondrial respiration and development of macrocytic anemia in mtDNA-mutator mice. These findings highlight a pathological feedback loop that explains how dysfunctional mitochondria can escape autophagy-mediated degradation and propagate in cells predisposed to somatic mtDNA mutations, leading to disease.

2015-04-21 | GSE57761 | GEO

The footprint of the aging stroma in older breast cancer patients.

Project description:Background: Tumoral masses are not only composed of malignant cells, but also enclose a more or less ample stromal micromilieu, which has been shown to influence the cancer cell behaviour. As aging induces accumulation of senescent cells in the body, this micromilieu is thought to be different in cancers occurring in old patients compared to the younger counterparts. More specifically, senescence-related fibroblastic features, such as the Senescence Associated Secretory Profile (SASP) and the induction of Autophagy, are suspected to stimulate tumor growth and progression. Methods: We compared gene expression profiles in stromal fields of breast carcinomas by performing laser capture microdissection of the cancer-associated stroma from 8 old (≥80 years at diagnosis) and 9 young (< 45 years at diagnosis) triple negative breast cancer patients. Gene expression data were obtained by microarray analysis (Affymetrix). Differential gene expression and Gene Set Enrichment Analysis (GSEA) were performed. Results: Differential gene expression analysis showed higher growth-, dedifferentiation- and migration- promoting gene expression in the stromal samples of older vs younger patients. GSEA confirmed the presence of a SASP, as well as the presence of Autophagy in the stroma of older patients. Conclusion: We provide the first evidence in humans that older age at diagnosis is associated with a different stromal micromilieu in breast cancers. The SASP and the presence of Autophagy appear to be important age-induced stromal features.

2016-11-26 | GSE90521 | GEO

Skeletal muscle “ex vivo” mitochondrial respiration parallels decline in vivo oxidative capacity, cardiorespiratory fitness and muscle strength: the Baltimore Longitudinal Study of Aging.

Project description:Mitochondrial function in human skeletal muscle declines with aging, possibly because of damage accumulation caused by reactive oxygen species (ROS) produced during oxidative phosphorylation. However, most evidence for such a decline comes from studies based on indirect methods and the clinical relevance of this decline with respect to physical function has not been clearly delineated. We hypothesized that mitochondrial respiration objectively assessed in permeabilized human muscle fibers declines with aging, correlates with phosphocreatine post exercise recovery rate (kPCr) assessed by 31P magnetic resonance spectroscopy (MRS) and with muscle performance and aerobic fitness. Mitochondrial respiration was assessed by high resolution respirometry in saponin-permeabilized fibers from vastus lateralis muscle biopsies of 38 participants from the Baltimore Longitudinal Study of Aging (BLSA) (21 men, age 24-91 years) who also had available measures of peak oxygen consumption (VO2max) from treadmill tests, gait speed in different tasks, 31P magnetic resonance spectroscopy and isokinetic knee extension strength. Results indicated a significant reduction in mitochondrial respiration in older age (p<0.05) that was independent of potential confounders. Mitochondrial respiratory capacity was also associated with VO2max, muscle strength, phosphocreatine post-exercise recovery rate (kPCr), and time in 400m walk (p < 0.05). A moderate negative trend toward significance (p = 0.074) was observed between mitochondrial respiration and BMI. Finally, transcriptional profiling revealed a downregulation of mitochondrial gene networks with aging (p < 0.05). Overall, our findings reinforce the notion that mitochondrial function declines with age and is implicated in the parallel decline of muscle performance and cardiorespiratory fitness.

2018-01-22 | GSE98613 | GEO

Expression and Prognostic impact of LncRNAs in AML

Project description:Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides located within the intergenic stretches or overlapping antisense transcripts of protein coding genes. LncRNAs are involved in numerous biological roles including imprinting, epigenetic regulation, apoptosis and cell-cycle. To determine whether lncRNAs are associated with clinical features and recurrent mutations in older patients (aged M-bM-^IM-%60 years) with cytogenetically normal (CN) acute myeloid leukemia (AML), we evaluated lncRNA expression in 148 untreated older CN-AML cases using a custom microarray platform. We analyzed 148 older cytogenetically normal(CN)-AML patients samples using a custom microarray platform and describe the expression of lncRNAs among the AML samples.

2014-11-26 | E-GEOD-63614 | biostudies-arrayexpress

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