The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches
Author(s)
Gruber, E; Kats, LM;
Details
Publication Year 2023-08-31,Volume 51,Issue #4,Page 1675-1686
Journal Title
Biochemical Society Transactions
Publication Type
Review
Abstract
Of the many genetic alterations that occur in cancer, relatively few have proven to be suitable for the development of targeted therapies. Mutations in isocitrate dehydrogenase (IDH) 1 and -2 increase the capacity of cancer cells to produce a normally scarce metabolite, D-2-hydroxyglutarate (2-HG), by several orders of magnitude. The discovery of the unusual biochemistry of IDH mutations spurred a flurry of activity that revealed 2-HG as an 'oncometabolite' with pleiotropic effects in malignant cells and consequences for anti-tumour immunity. Over the next decade, we learned that 2-HG dysregulates a wide array of molecular pathways, among them a large family of dioxygenases that utilise the closely related metabolite alpha-ketoglutarate (alpha-KG) as an essential co-substrate. 2-HG not only contributes to malignant transformation, but some cancer cells become addicted to it and sensitive to inhibitors that block its synthesis. Moreover, high 2-HG levels and loss of wild-type IDH1 or IDH2 activity gives rise to synthetic lethal vulnerabilities. Herein, we review the biology of IDH mutations with a particular focus on acute myeloid leukaemia (AML), an aggressive disease where selective targeting of IDH-mutant cells is showing significant promise.
Publisher
Portland Press
Keywords
Humans; *Leukemia, Myeloid, Acute/drug therapy/genetics; Mutation; Ketoglutaric Acids; Cell Transformation, Neoplastic; Isocitrate Dehydrogenase/genetics; 2-hg; IDH mutation; acute myeloid leukaemia; targeted therapies
Department(s)
Laboratory Research
PubMed ID
37526143
Open Access at Publisher's Site
https://doi.org/10.1042/bst20230017
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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Last Modified: 2023-10-31 06:08:17

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