组蛋白去甲基化酶KDM5C通过稳定脑啡肽增强急性髓系白血病细胞对来那度胺的敏感性。

The histone demethylase KDM5C enhances the sensitivity of acute myeloid leukemia cells to lenalidomide by stabilizing cereblon.

作者信息

Zou Lu, Cao Dan, Sun Qing, Yu Wenjun, Li Bingzong, Xu Guoqiang, Zhou Liang

机构信息

Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, 199 Ren'ai Road, Suzhou, 215123, Jiangsu, China.

Department of Hematology, The Second Affiliated Hospital of Soochow University, San Xiang Road 1055, Suzhou, 215006, China.

出版信息

Cell Mol Biol Lett. 2025 Jan 29;30(1):14. doi: 10.1186/s11658-025-00697-8.

DOI:10.1186/s11658-025-00697-8

PMID:39881283

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11780777/

Abstract

BACKGROUND

The protein cereblon (CRBN) mediates the antileukemia effect of lenalidomide (Len). Len binds to CRBN, recruits IKZF1/IKZF3, and promotes their ubiquitination and degradation, through which Len exhibits its antileukemia and antimyeloma activity. Therefore, the protein level of CRBN might affect the antiproliferative effect of Len. In this study, we explored the interactome for CRBN using proximity labeling technique TurboID and quantitative proteomics, and then investigated the antileukemia effect of Len.

METHODS

The primary acute myeloid leukemia (AML) cells and AML cell lines were used to explore the functions of histone demethylase KDM5C on the antileukemia effect of Len. The cell viability and CRBN protein levels were evaluated in these cell lines. In addition, the KDM5C inhibitors were used to determine the effects of KDM5C enzymatic activity on the viability of AML cell lines.

RESULTS

We identified that histone demethylase KDM5C was a CRBN-interacting protein. Biochemical experiments found that the CRBN-interacting protein KDM5C could stabilize CRBN and enhance the antileukemia effect of Len in an enzyme activity-independent manner. Furthermore, our studies revealed that the small-molecule compound MLN4924 could increase CRBN by elevating KDM5C.The combination of MLN4924 and Len can further increase the sensitivity of primary AML cells and AML cell lines to Len.

CONCLUSIONS

This study provides a possible strategy for a combination treatment with MLN4924 and Len for leukemia.

摘要

背景

蛋白质cereblon（CRBN）介导来那度胺（Len）的抗白血病作用。Len与CRBN结合，招募IKZF1/IKZF3，并促进它们的泛素化和降解，Len通过这种方式发挥其抗白血病和抗骨髓瘤活性。因此，CRBN的蛋白质水平可能会影响Len的抗增殖作用。在本研究中，我们使用邻近标记技术TurboID和定量蛋白质组学探索了CRBN的相互作用组，然后研究了Len的抗白血病作用。

方法

使用原发性急性髓系白血病（AML）细胞和AML细胞系来探索组蛋白去甲基化酶KDM5C对Len抗白血病作用的影响。评估这些细胞系中的细胞活力和CRBN蛋白水平。此外，使用KDM5C抑制剂来确定KDM5C酶活性对AML细胞系活力的影响。

结果

我们鉴定出组蛋白去甲基化酶KDM5C是一种与CRBN相互作用的蛋白质。生化实验发现，与CRBN相互作用的蛋白质KDM5C可以稳定CRBN，并以不依赖酶活性的方式增强Len的抗白血病作用。此外，我们的研究表明，小分子化合物MLN4924可以通过提高KDM5C来增加CRBN。MLN4924和Len联合使用可以进一步提高原发性AML细胞和AML细胞系对Len的敏感性。