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RIPK3 deficiency blocks R-2-hydroxyglutarate-induced necroptosis in IDH-mutated AML cells.
Zhu, Shuanghong; Luo, Yingwan; Li, Kongfei; Mei, Chen; Wang, Yuxia; Jiang, Lingxu; Wang, Wei; Zhang, Qi; Yang, Wenli; Lang, Wei; Zhou, Xinping; Wang, Lu; Ren, Yanling; Ma, Liya; Ye, Li; Huang, Xin; Chen, Jianjun; Sun, Jie; Tong, Hongyan.
Afiliación
  • Zhu S; Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
  • Luo Y; Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China.
  • Li K; Zhejiang Provincial Clinical Research Center for Hematological Disorders, Hangzhou, Zhejiang, PR China.
  • Mei C; Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
  • Wang Y; Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China.
  • Jiang L; Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
  • Wang W; Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China.
  • Zhang Q; Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
  • Yang W; Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China.
  • Lang W; Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
  • Zhou X; Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China.
  • Wang L; Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
  • Ren Y; Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China.
  • Ma L; Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
  • Ye L; Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China.
  • Huang X; Zhejiang Provincial Clinical Research Center for Hematological Disorders, Hangzhou, Zhejiang, PR China.
  • Chen J; Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China.
  • Sun J; Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University, Hangzhou, Zhejiang, PR China.
  • Tong H; Zhejiang Provincial Clinical Research Center for Hematological Disorders, Hangzhou, Zhejiang, PR China.
Sci Adv ; 10(16): eadi1782, 2024 Apr 19.
Article en En | MEDLINE | ID: mdl-38630819
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Glutaratos / Lisina Límite: Humans Idioma: En Revista: Sci Adv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Glutaratos / Lisina Límite: Humans Idioma: En Revista: Sci Adv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos