The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate
Patrick S. Ward,Jay P. Patel,David R. Wise,Omar Abdel-Wahab,Bryson D. Bennett,Hilary A. Coller,Justin R. Cross,Valeria Fantin,Cyrus V. Hedvat,Alexander E. Perl,Joshua D. Rabinowitz,Martin Carroll,Shinsan M. Su,Kim A. Sharp,Ross L. Levine,Craig B. Thompson +15 more
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TLDR
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.About:
This article is published in Cancer Cell.The article was published on 2010-03-16 and is currently open access. It has received 1790 citations till now. The article focuses on the topics: Enasidenib & IDH2.read more
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Cancer Genome Landscapes
Bert Vogelstein,Nickolas Papadopoulos,Victor E. Velculescu,Shibin Zhou,Luis A. Diaz,Kenneth W. Kinzler +5 more
TL;DR: This work has revealed the genomic landscapes of common forms of human cancer, which consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of "hills" (Genes altered infrequently).
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Regulation of cancer cell metabolism
TL;DR: Interest in the topic of tumour metabolism has waxed and waned over the past century, but it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.
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The Emerging Hallmarks of Cancer Metabolism
TL;DR: This Perspective has organized known cancer-associated metabolic changes into six hallmarks: deregulated uptake of glucose and amino acids, use of opportunistic modes of nutrient acquisition, useof glycolysis/TCA cycle intermediates for biosynthesis and NADPH production, increased demand for nitrogen, alterations in metabolite-driven gene regulation, and metabolic interactions with the microenvironment.
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Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
TL;DR: It is argued that altered metabolism has attained the status of a core hallmark of cancer.
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Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation.
Maria E. Figueroa,Omar Abdel-Wahab,Chao Lu,Patrick S. Ward,Jay P. Patel,Alan Shih,Yushan Li,Neha Bhagwat,Aparna Vasanthakumar,Hugo F. Fernandez,Martin S. Tallman,Zhuoxin Sun,Kristy L. Wolniak,Justine K. Peeters,Wei Liu,Sung E. Choe,Valeria Fantin,Elisabeth Paietta,Bob Löwenberg,Jonathan D. Licht,Lucy A. Godley,Ruud Delwel,Peter J. M. Valk,Craig B. Thompson,Ross L. Levine,Ari Melnick +25 more
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.
References
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IDH1 and IDH2 Mutations in Gliomas
Hai Yan,D. Williams Parsons,Genglin Jin,Roger E. McLendon,B.K. Ahmed Rasheed,Weishi Yuan,Ivan Kos,Ines Batinic-Haberle,Siân Jones,Gregory J. Riggins,Henry S. Friedman,Allan H. Friedman,David A. Reardon,James E. Herndon,Kenneth W. Kinzler,Victor E. Velculescu,Bert Vogelstein,Darell D. Bigner +17 more
TL;DR: Mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.
Journal ArticleDOI
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Lenny Dang,David W. White,Stefan Gross,Bryson D. Bennett,Mark A. Bittinger,Edward M. Driggers,Valeria Fantin,Hyun Gyung Jang,Shengfang Jin,Marie C. Keenan,Kevin Marks,Robert M. Prins,Patrick S. Ward,Katharine E. Yen,Linda M. Liau,Joshua D. Rabinowitz,Lewis C. Cantley,Craig B. Thompson,Matthew G. Vander Heiden,Matthew G. Vander Heiden,Shinsan M. Su +20 more
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.
PatentDOI
Consensus coding sequences of human breast and colorectal cancers
Tobias Sjöblom,Sian Jones,D. Williams Parsons,Laura D. Wood,Jimmy Lin,Thomas D. Barber,Diana Mandelker,Bert Vogelstein,Kenneth W. Kinzler,Victor E. Velculesu +9 more
TL;DR: In this paper, the authors analyzed 13,023 genes in 11 breast and 11 colorectal cancers and found that individual tumors accumulate an average of 90 mutant genes but only a subset of these contribute to the neoplastic process.
Journal ArticleDOI
Beyond aerobic glycolysis : Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis
Ralph J. DeBerardinis,Anthony A. Mancuso,Evgueni Daikhin,Ilana Nissim,Marc Yudkoff,Suzanne Wehrli,Craig B. Thompson +6 more
TL;DR: Transformed cells exhibit a high rate of glutamine consumption that cannot be explained by the nitrogen demand imposed by nucleotide synthesis or maintenance of nonessential amino acid pools, and glutamine metabolism provides a carbon source that facilitates the cell's ability to use glucose-derived carbon and TCA cycle intermediates as biosynthetic precursors.
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