Institution
Agios Pharmaceuticals
About: Agios Pharmaceuticals is a based out in . It is known for research contribution in the topics: Isocitrate dehydrogenase & Myeloid leukemia. The organization has 354 authors who have published 381 publications receiving 28064 citations. The organization is also known as: Agios Pharmaceuticals, Inc. & Agios Pharmaceuticals (United States).
Topics: Isocitrate dehydrogenase, Myeloid leukemia, IDH1, IDH2, Pyruvate kinase
Papers
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TL;DR: It is shown that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG), and that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
Abstract: Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
3,508 citations
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TL;DR: Mutational and epigenetic profiling of a large acute myeloid leukemia (AML) patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specificHypermethylation signature, suggesting a shared proleukemogenic effect.
2,372 citations
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TL;DR: It is reported that tumor 2HG is elevated in a high percentage of patients with cytogenetically normal acute myeloid leukemia (AML), and AML patients with IDH mutations display a significantly reduced number of other well characterized AML-associated mutations and/or associated chromosomal abnormalities, potentially implicating IDH mutation in a distinct mechanism of AML pathogenesis.
1,790 citations
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TL;DR: An integrated high-throughput transcriptional-metabolic profiling and analysis pipeline provides a highly integrated picture of the physiological modules supporting macrophage polarization, identifying potential pharmacologic control points for both macrophages.
1,298 citations
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TL;DR: Results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets.
Abstract: Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation. RNA interference (RNAi)-based loss-of-function screening has proven powerful for the identification of new and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumour suppressor genes. Here we developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, we screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of oestrogen receptor (ER)-negative breast cancers. PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis. We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of α-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. These results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets.
1,248 citations
Authors
Showing all 354 results
Name | H-index | Papers | Citations |
---|---|---|---|
Matthew G. Vander Heiden | 97 | 281 | 56483 |
Thomas Winkler | 53 | 201 | 10662 |
David P. Schenkein | 48 | 132 | 15667 |
Darrell R. Borger | 39 | 104 | 5400 |
Katharine E. Yen | 34 | 70 | 10879 |
Eyal C. Attar | 33 | 111 | 4742 |
Stefan Gross | 30 | 63 | 8086 |
Lenny Dang | 30 | 61 | 10429 |
Lipika Goyal | 29 | 169 | 5025 |
Patrick A. J. Haslett | 29 | 51 | 3704 |
Wei Liu | 28 | 48 | 8465 |
Sung Choe | 26 | 53 | 2564 |
Valeria Fantin | 24 | 52 | 10578 |
Zi Peng Fan | 24 | 35 | 5723 |
Byron DeLaBarre | 23 | 31 | 2913 |