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

Dong Chen, Siyuan Xia, Mei Wang, Ruiting Lin, Yuancheng Li, Hui Mao, Mike Aguiar, Christopher A. Famulare, Alan H. Shih, Cameron W. Brennan, Xue Gao, Yaozhu Pan, Shuangping Liu, Jun Fan, Lingtao Jin, Lina Song, An Zhou, Joydeep Mukherjee, Russell O. Pieper, Ashutosh MishraJunmin Peng, Martha Arellano, William G. Blum, Sagar Lonial, Titus J. Boggon, Ross L. Levine, Jing Chen

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)756-777
Number of pages22
JournalCancer Discovery
Volume9
Issue number6
DOIs
StatePublished - Jun 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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