Idh2-KO Mouse

Idh2, isocitrate dehydrogenase 2, is an enzyme located in the mitochondria. It catalyzes the oxidative decarboxylation of isocitrate to α -ketoglutarate, playing a crucial role in the tricarboxylic acid (TCA) cycle, a key metabolic pathway [4,5,6]. Mutations in Idh2 are associated with several diseases, highlighting its biological importance in maintaining normal cellular functions, and genetic models can be valuable for studying its functions [3,5,6].

Mutations in Idh2 occur in various cancers. In gliomas, mutations affecting amino acid R172 are found in tumors without Idh1 mutations, and such tumors have distinct genetic and clinical characteristics, with patients having a better outcome than those with wild-type Idh genes [1]. In acute myeloid leukemia (AML), Idh2 mutations lead to DNA hypermethylation, aberrant gene expression, cell proliferation, and abnormal differentiation. Targeting mutant Idh2 has opened new treatment avenues [3]. In urothelial cancer, gain-of-function of Idh2 stabilizes Hif-1α-induced metabolic reprogramming, promoting chemoresistance, and downregulation or pharmacological suppression of Idh2 restores chemosensitivity [2].

In conclusion, Idh2 is essential for the TCA cycle and normal cellular metabolism. Mutations in Idh2 are linked to cancers like gliomas, AML, and urothelial cancer. Understanding Idh2 through genetic models can provide insights into disease mechanisms and potentially lead to better treatment strategies for these malignancies.

References:

1. Yan, Hai, Parsons, D Williams, Jin, Genglin, Vogelstein, Bert, Bigner, Darell D. . IDH1 and IDH2 mutations in gliomas. In The New England journal of medicine, 360, 765-73. doi:10.1056/NEJMoa0808710. https://pubmed.ncbi.nlm.nih.gov/19228619/

2. Shigeta, Keisuke, Hasegawa, Masanori, Hishiki, Takako, Kosaka, Takeo, Oya, Mototsugu. 2023. IDH2 stabilizes HIF-1α-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer. In The EMBO journal, 42, e110620. doi:10.15252/embj.2022110620. https://pubmed.ncbi.nlm.nih.gov/36637036/

3. Babakhanlou, Rodrick, DiNardo, Courtney, Borthakur, Gautam. 2023. IDH2 mutations in acute myeloid leukemia. In Leukemia & lymphoma, 64, 1733-1741. doi:10.1080/10428194.2023.2237153. https://pubmed.ncbi.nlm.nih.gov/37462435/

4. Stein, Eytan M. 2015. IDH2 inhibition in AML: Finally progress? In Best practice & research. Clinical haematology, 28, 112-5. doi:10.1016/j.beha.2015.10.016. https://pubmed.ncbi.nlm.nih.gov/26590767/

5. Amaya, Maria L, Pollyea, Daniel A. 2018. Targeting the IDH2 Pathway in Acute Myeloid Leukemia. In Clinical cancer research : an official journal of the American Association for Cancer Research, 24, 4931-4936. doi:10.1158/1078-0432.CCR-18-0536. https://pubmed.ncbi.nlm.nih.gov/29769206/

6. Nayarisseri, Anuraj, Bandaru, Srinivas, Khan, Arshiya, Mendonça Junior, Francisco Jaime Bezerra, Singh, Sanjeev Kumar. 2024. Epigenetic dysregulation in cancers by isocitrate dehydrogenase 2 (IDH2). In Advances in protein chemistry and structural biology, 141, 223-253. doi:10.1016/bs.apcsb.2023.12.012. https://pubmed.ncbi.nlm.nih.gov/38960475/