Integration of genomics and metabolomics in acute myeloid leukemia
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PROVIDER: EGAS00001005422 | EGA |
REPOSITORIES: EGA
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Project description:Background: Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Methods: Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Results: Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. Conclusions: These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.
2023-11-09 | GSE247025 | GEO
Project description:Mutations in CCAAT/enhancer binding protein alpha (CEBPA) are seen in 5-14% of acute myeloid leukemia (AML) and have been associated with a favorable clinical outcome. Most AMLs with CEBPA mutations simultaneously carry two mutations (CEBPAdouble-mut), usually biallelic, while single heterozygous mutations (CEBPAsingle-mut) are less frequently seen. Using denaturing high performance liquid chromatography and nucleotide sequencing we identified among a cohort of 598 newly diagnosed AMLs a subset of 41 CEBPA mutant cases, i.e. 28 CEBPAdouble-mut and 13 CEBPAsingle-mut cases. CEBPAdouble-mut associated with a unique gene expression profile as well as favorable overall and event-free survival, retained in multivariable analysis that included cytogenetic risk, FLT3-ITD and NPM1 mutation, white blood cell count and age. In contrast, CEBPAsingle-mut AMLs did not express a discriminating signature and could not be distinguished from wild type cases as regards clinical outcome. These results demonstrate significant underlying heterogeneity within CEBPA mutation positive AML with prognostic relevance. Experiment Overall Design: Gene expression profiling of 524 cases of de novo AML. Comparisons of cases with double and single CEBPA mutations versus those with wild type CEBPA.
2009-01-23 | E-GEOD-14468 | biostudies-arrayexpress
Project description:Mutations in CCAAT/enhancer binding protein alpha (CEBPA) are seen in 5-14% of acute myeloid leukemia (AML) and have been associated with a favorable clinical outcome. Most AMLs with CEBPA mutations simultaneously carry two mutations (CEBPAdouble-mut), usually biallelic, while single heterozygous mutations (CEBPAsingle-mut) are less frequently seen. Using denaturing high performance liquid chromatography and nucleotide sequencing we identified among a cohort of 598 newly diagnosed AMLs a subset of 41 CEBPA mutant cases, i.e. 28 CEBPAdouble-mut and 13 CEBPAsingle-mut cases. CEBPAdouble-mut associated with a unique gene expression profile as well as favorable overall and event-free survival, retained in multivariable analysis that included cytogenetic risk, FLT3-ITD and NPM1 mutation, white blood cell count and age. In contrast, CEBPAsingle-mut AMLs did not express a discriminating signature and could not be distinguished from wild type cases as regards clinical outcome. These results demonstrate significant underlying heterogeneity within CEBPA mutation positive AML with prognostic relevance. Keywords: Gene expression profiling by arrays
2009-01-21 | GSE14468 | GEO
Project description:Through integration of whole genome CRISPR screening and pan-cancer genetic dependency mapping, we identified nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) as acute myeloid leukemia (AML) dependencies governing NAD+ biosynthesis. While both NAMPT and NMNAT1 were required for AML, we found that the presence of NAD+ precursors bypassed the dependence of AML on NAMPT, but not NMNAT1, pointing to NMNAT1 as a gatekeeper of NAD+ biosynthesis. We provide evidence that reduced nuclear NAD+ upon deletion of NMNAT1 activated p53, which is due to attenuated deacetylation by SIRT6/7 in AML cells. Our findings reveal that NAD+ is a critical metabolic foundation for AML, and NMNAT1 is a novel therapeutic target for this disease.
2021-07-28 | GSE171565 | GEO
Project description:Metabolic pathways are now considered as intrinsic virulence attributes of pathogenic bacteria and hence represent potential targets for anti-bacterial strategies. Here, we addressed the role of the pentose phosphate pathway (PPP) and its connections with other metabolic pathways in the pathophysiology of Francisella novicida. We have previously shown that this intracellular bacterial pathogen used gluconeogenesis to metabolize host-derived nutrients in the cytosolic compartment of infected macrophages. Francisella species, which lacks the oxidative branch of the PPP, are equipped with all the genes of the non-oxidative branch (i.e. tktA, tal, rpiA and rpe, encoding transketolase, transaldolase, ribose-phosphate isomerase and ribulose phosphate epimerase, respectively). The involvement of the PPP in the early stage of intracellular life cycle of F. novicida was first demonstrated with the study of PPP inactivation mutants. Indeed, inactivation of tktA, rpiA or rpe genes, severely impaired intramacrophagic multiplication during the first 24–hours. However, time-lapse video microscopy demonstrated that rpiA and rpe mutants were able to resume late intracellular bacterial multiplication. To get further insight into the links between the PPP and other metabolic networks of the bacterium, we next performed a thorough proteo-metabolomic analysis of these mutants. We show that the PPP constitutes a major bacterial metabolic hub with multiple connections with glycolysis, tricarboxylic acid cycle and other metabolic pathways, such as fatty acid degradation and sulfur metabolism. Hence, our study highlights how, by its multiple connections with other metabolic pathways, PPP is instrumental to Francisella pathogenesis and growth in its intracellular niche.
2021-07-27 | PXD023550 | Pride
Project description:Acute myeloid leukemia (AML) is a heterogeneous and deadly disease characterized by uncontrolled expansion of malignant blasts. The current treatment for AML patients includes intensive chemotherapy and high-risk hematopoietic stem cell transplantation, highlighting the need for less toxic and more effective therapies. Altered metabolism and dysregulated microRNA (miRNA) expression profiles are characteristic of AML. However, there is a paucity of studies exploring how changes in the metabolic state of the leukemic cells regulate miRNA expression leading to altered cellular behavior. Here, we blocked pyruvate entry into mitochondria by deleting the Mitochondria Pyruvate Carrier (MPC1) gene in MV4-11 and Molm-14 human AML cell lines, which decreased Oxidative Phosphorylation (OXPHOS). The loss of MPC1 led to increased expression of miR-1 in both human AML cell lines tested. AML patient sample analysis showed that higher miR-1 expression correlates with reduced survival. Transcriptional and metabolic profiling of miR-1 overexpressing AML cells revealed that miR-1 increased OXPHOS, along with key metabolites that fuel the TCA cycle such as glutamine and fumaric acid. Inhibition of glutaminolysis decreased the elevated OXPHOS in miR-1 overexpressing MV4-11 cells, highlighting that miR-1 regulates OXPHOS through glutaminolysis. Further, the overexpression of miR-1 in AML cells exacerbated disease in a mouse xenograft model. Our work expands current knowledge within the field by uncovering novel connections between AML cell metabolism and miRNA expression that facilitates disease progression. Together, our work points to miR-1 as a potential new therapeutic target that can be used to disrupt AML cell metabolism and thus pathogenesis.
2023-08-11 | GSE220133 | GEO
Project description:Acute myeloid leukemia (AML) is a heterogeneous and deadly disease characterized by uncontrolled expansion of malignant blasts. The current treatment for AML patients includes intensive chemotherapy and high-risk hematopoietic stem cell transplantation, highlighting the need for less toxic and more effective therapies. Altered metabolism and dysregulated microRNA (miRNA) expression profiles are characteristic of AML. However, there is a paucity of studies exploring how changes in the metabolic state of the leukemic cells regulate miRNA expression leading to altered cellular behavior. Here, we blocked pyruvate entry into mitochondria by deleting the Mitochondria Pyruvate Carrier (MPC1) gene in MV4-11 and Molm-14 human AML cell lines, which decreased Oxidative Phosphorylation (OXPHOS). The loss of MPC1 led to increased expression of miR-1 in both human AML cell lines tested. AML patient sample analysis showed that higher miR-1 expression correlates with reduced survival. Transcriptional and metabolic profiling of miR-1 overexpressing AML cells revealed that miR-1 increased OXPHOS, along with key metabolites that fuel the TCA cycle such as glutamine and fumaric acid. Inhibition of glutaminolysis decreased the elevated OXPHOS in miR-1 overexpressing MV4-11 cells, highlighting that miR-1 regulates OXPHOS through glutaminolysis. Further, the overexpression of miR-1 in AML cells exacerbated disease in a mouse xenograft model. Our work expands current knowledge within the field by uncovering novel connections between AML cell metabolism and miRNA expression that facilitates disease progression. Together, our work points to miR-1 as a potential new therapeutic target that can be used to disrupt AML cell metabolism and thus pathogenesis.
2023-08-11 | GSE220126 | GEO
Project description:U4/U6 di-snRNPs were disrupted and singular U4 and U6 snRNPs accumulated in egy mutant embryos, establishing the recycling function of p110 in vivo. Based on microarray analyses, a subset of spliceosome components and splicing-related factors was coordinately upregulated in the egy mutant. This revealed an extensive network of coregulated components of the spliceosome cycle, compensating – albeit inefficiently – for the recycling defect. In contrast, another set of genes, many of them eye- and pancreas-specific, was downregulated in the egy mutant embryos. Keywords: mut / wt comparison
2007-01-31 | GSE5586 | GEO
Project description:Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA, in the chronic and acute settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut-/-;TgINS-MCK-Mut mice accurately replicate the hepato-renal mitochondriopathy and growth failure seen in severely affected patients, and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and responded abberrantly to fasting when compared to controls.
2019-08-01 | GSE118862 | GEO
Project description:Perturbations in intermediary metabolism contribute to the pathogenesis of acute myeloid leukemia (AML) and can produce therapeutically actionable dependencies. Here, we probed whether alpha-ketoglutarate (aKG) metabolism represents a specific vulnerability in AML. Using functional genomics, metabolomics, and mouse models, we identified the aKG dehydrogenase complex, which catalyzes the conversion of aKG to succinyl CoA, as a molecular dependency across multiple models of adverse-risk AML. Inhibition of 2-oxoglutarate dehydrogenase (OGDH), the E1 subunit of the aKG dehydrogenase complex, impaired AML progression and drove differentiation. Mechanistically, hindrance of aKG flux through the tricarboxylic acid (TCA) cycle resulted in rapid exhaustion of aspartate pools and blockade of de novo nucleotide biosynthesis, while cellular bioenergetics was largely preserved. Additionally, increased aKG levels following OGDH inhibition impacted the biosynthesis of other critical amino acids. Thus, this work has identified a previously undescribed, functional link between certain TCA cycle components and nucleotide biosynthesis enzymes across AML. This metabolic node may serve as a cancer-specific vulnerability amenable to therapeutic targeting in AML and perhaps in other cancers with similar metabolic wiring.
2024-11-27 | GSE282980 | GEO