2. Academic Validation
  3. RIPK3 deficiency blocks R-2-hydroxyglutarate-induced necroptosis in IDH-mutated AML cells

RIPK3 deficiency blocks R-2-hydroxyglutarate-induced necroptosis in IDH-mutated AML cells

  • Sci Adv. 2024 Apr 19;10(16):eadi1782. doi: 10.1126/sciadv.adi1782.
Shuanghong Zhu 1 2 3,  Yingwan Luo 1 2,  Kongfei Li 1 2,  Chen Mei 1 2,  Yuxia Wang 1 2,  Lingxu Jiang 1 2,  Wei Wang 1 2 3,  Qi Zhang 1 2 3,  Wenli Yang 1 2 3,  Wei Lang 1 2 3,  Xinping Zhou 1 2,  Lu Wang 1 2 3,  Yanling Ren 1 2,  Liya Ma 1 2,  Li Ye 1 2,  Xin Huang 1 2 3,  Jianjun Chen 4 5,  Jie Sun 1 3 6,  Hongyan Tong 1 2 3 6
Affiliations

Affiliations

  • 1 Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
  • 2 Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China.
  • 3 Zhejiang Provincial Clinical Research Center for Hematological Disorders, Hangzhou, Zhejiang, PR China.
  • 4 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • 5 Gehr Family Center for Leukemia Research, City of Hope Medical Center and Comprehensive Cancer Center, Duarte, CA 91010, USA.
  • 6 Zhejiang University Cancer Center, Hangzhou, Zhejiang, PR China.
PMID: 38630819 DOI: 10.1126/sciadv.adi1782
Abstract

Mutant isocitrate dehydrogenases (IDHs) produce R-2-hydroxyglutarate (R-2HG), which inhibits the growth of most acute myeloid leukemia (AML) cells. Here, we showed that Necroptosis, a form of programmed cell death, contributed to the antileukemia activity of R-2HG. Mechanistically, R-2HG competitively inhibited the activity of lysine demethylase 2B (KDM2B), an α-ketoglutarate-dependent dioxygenase. KDM2B inhibition increased histone 3 lysine 4 trimethylation levels and promoted the expression of receptor-interacting protein kinase 1 (RIPK1), which consequently caused Necroptosis in AML cells. The expression of RIPK3 was silenced because of DNA methylation in IDH-mutant (mIDH) AML cells, resulting in R-2HG resistance. Decitabine up-regulated RIPK3 expression and repaired endogenous R-2HG-induced Necroptosis pathway in mIDH AML cells. Together, R-2HG induced RIPK1-dependent Necroptosis via KDM2B inhibition in AML cells. The loss of RIPK3 protected mIDH AML cells from Necroptosis. Restoring RIPK3 expression to exert R-2HG's intrinsic antileukemia effect will be a potential therapeutic strategy in patients with AML.

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