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Cancer Discov. 2019 Mar 12. doi: 10.1158/2159-8290.CD-18-1040. [Epub ahead of print]

Mutant and Wild-Type Isocitrate Dehydrogenase 1 Share Enhancing Mechanisms Involving Distinct Tyrosine Kinase Cascades in Cancer.

Author information

1
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
2
Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
3
Department of Pharmacy, Children's Hospital of Soochow University, Suzhou, China.
4
Department of Radiology and Imaging Sciences, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
5
Cell Signaling Technology, Inc., Danvers, Massachusetts.
6
Memorial Sloan Kettering Cancer Center, New York, New York.
7
General Hospital of Lanzhou Military Region, Lanzhou, China.
8
Department of Pathology, Medical College, Dalian University, Dalian, China.
9
Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
10
Department of Neurobiology, Morehouse School of Medicine, Atlanta, Georgia.
11
Department of Neurological Surgery, University of California, San Francisco, California.
12
Department of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee.
13
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut.
14
Memorial Sloan Kettering Cancer Center, New York, New York. leviner@mskcc.org jchen@emory.edu.
15
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia. leviner@mskcc.org jchen@emory.edu.
#
Contributed equally

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.

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