The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches

Gruber, E; Kats, LM

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
Publisher's Version: https://doi.org/10.1042/BST20230017
Open Access at Publisher's Site: https://doi.org/10.1042/bst20230017
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-10-31 06:07:50

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