RIPK3 deficiency blocks R-2-hydroxyglutarate–induced necroptosis in IDH-mutated AML cells-Reference-Cited by-同舟云学术

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

Published:2024-04-19 Issue:16 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Zhu Shuanghong¹²³^ORCID,Luo Yingwan¹²^ORCID,Li Kongfei¹²^ORCID,Mei Chen¹²^ORCID,Wang Yuxia¹²^ORCID,Jiang Lingxu¹²^ORCID,Wang Wei¹²³^ORCID,Zhang Qi¹²³^ORCID,Yang Wenli¹²³^ORCID,Lang Wei¹²³^ORCID,Zhou Xinping¹²^ORCID,Wang Lu¹²³^ORCID,Ren Yanling¹²^ORCID,Ma Liya¹²^ORCID,Ye Li¹²^ORCID,Huang Xin¹²³^ORCID,Chen Jianjun⁴⁵^ORCID,Sun Jie¹³⁶^ORCID,Tong Hongyan¹²³⁶^ORCID

Affiliation:

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.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adi1782

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