Mutant and wild-type isocitrate dehydrogenase 1 share enhancing mechanisms involving distinct tyrosine kinase cascades in cancer Journal Article


Authors: Chen, D.; Xia, S.; Wang, M.; Lin, R.; Li, Y.; Mao, H.; Aguiar, M.; Famulare, C. A.; Shih, A. H.; Brennan, C. W.; Gao, X.; Pan, Y.; Liu, S.; Fan, J.; Jin, L.; Song, L.; Zhou, A.; Mukherjee, J.; Pieper, R. O.; Mishra, A.; Peng, J.; Arellano, M.; Blum, W. G.; Lonial, S.; Boggon, T. J.; Levine, R. L.; Chen, J.
Article Title: Mutant and wild-type isocitrate dehydrogenase 1 share enhancing mechanisms involving distinct tyrosine kinase cascades in cancer
Abstract: Isocitrate dehydrogenase 1 (IDH1) is important for reductive carboxylation in cancer cells, and the IDH1 R132H mutation plays a pathogenic role in cancers including acute myeloid leukemia (AML). However, the regulatory mechanisms modulating mutant and/or wild-type (WT) IDH1 function remain unknown. Here, we show that two groups of tyrosine kinases (TK) enhance the activation of mutant and WT IDH1 through preferential Y42 or Y391 phosphorylation. Mechanistically, Y42 phosphorylation occurs in IDH1 monomers, which promotes dimer formation with enhanced substrate (isocitrate or α-ketoglutarate) binding, whereas Y42-phosphorylated dimers show attenuated disruption to monomers. Y391 phosphorylation occurs in both monomeric and dimeric IDH1, which enhances cofactor (NADP+ or NADPH) binding. Diverse oncogenic TKs phosphorylate IDH1 WT at Y42 and activate Src to phosphorylate IDH1 at Y391, which contributes to reductive carboxylation and tumor growth, whereas FLT3 or the FLT3-ITD mutation activates JAK2 to enhance mutant IDH1 activity through phosphorylation of Y391 and Y42, respectively, in AML cells. SIGNIFICANCE: We demonstrated an intrinsic connection between oncogenic TKs and activation of WT and mutant IDH1, which involves distinct TK cascades in related cancers. In particular, these results provide an additional rationale supporting the combination of FLT3 and mutant IDH1 inhibitors as a promising clinical treatment of mutant IDH1-positive AML.See related commentary by Horton and Huntly, p. 699.This article is highlighted in the In This Issue feature, p. 681. ©2019 American Association for Cancer Research.
Journal Title: Cancer Discovery
Volume: 9
Issue: 6
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2019-06-01
Start Page: 756
End Page: 777
Language: English
DOI: 10.1158/2159-8290.Cd-18-1040
PUBMED: 30862724
PROVIDER: scopus
PMCID: PMC6548588
DOI/URL:
Notes: Article -- Source: Scopus
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MSK Authors
  1. Cameron Brennan
    184 Brennan
  2. Alan H Shih
    58 Shih
  3. Ross Levine
    620 Levine