Cytoplasmic TP53INP2 acts as an apoptosis partner in TRAIL treatment: the synergistic effect of TRAIL with venetoclax in TP53INP2-positive acute myeloid leukemia

作者全名：Ren, Jun; Huang, Junpeng; Yang, Zailin; Sun, Minghui; Yang, Jing; Lin, Can; Jin, Fangfang; Liu, Yongcan; Tang, Lisha; Hu, Jiayuan; Wei, Xingyu; Chen, Xinyi; Yuan, Zihao; Yang, Zesong; Chen, Yanmeng; Zhang, Ling

作者地址：[Ren, Jun; Huang, Junpeng; Sun, Minghui; Yang, Jing; Lin, Can; Jin, Fangfang; Liu, Yongcan; Tang, Lisha; Hu, Jiayuan; Wei, Xingyu; Chen, Xinyi; Yuan, Zihao; Chen, Yanmeng; Zhang, Ling] Chongqing Med Univ, Coll Lab Med, Key Lab Lab Med Diag, Minist Educ, Chongqing 400016, Peoples R China; [Yang, Zailin] Chongqing Univ, Canc Hosp, Dept Hematol Oncol, Chongqing Key Lab Translat Res Canc Metastasis & I, Chongqing 400030, Peoples R China; [Yang, Zesong] Chongqing Med Univ, Dept Hematol, Affiliated Hosp 1, Chongqing 400016, Peoples R China

通信作者：Chen, YM; Zhang, L (通讯作者)，Chongqing Med Univ, Coll Lab Med, Key Lab Lab Med Diag, Minist Educ, Chongqing 400016, Peoples R China.

来源：JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001251896300001

JCR分区：Q1

影响因子：11.4

年份：2024

卷号：43

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Acute myeloid leukemia; TRAIL; TP53INP2; Venetoclax; Nucleophosmin 1

摘要：Background Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor outcomes, especially in older AML patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered a promising anticancer drug because it selectively induces the extrinsic apoptosis of tumor cells without affecting normal cells. However, clinical trials have shown that the responses of patients to TRAIL are significantly heterogeneous. It is necessary to explore predictable biomarkers for the preselection of AML patients with better responsiveness to TRAIL. Here, we investigated the critical role of tumor protein p53 inducible nuclear protein 2 (TP53INP2) in the AML cell response to TRAIL treatment.Methods First, the relationship between TP53INP2 and the sensitivity of AML cells to TRAIL was determined by bioinformatics analysis of Cancer Cell Line Encyclopedia datasets, Cell Counting Kit-8 assays, flow cytometry (FCM) and cell line-derived xenograft (CDX) mouse models. Second, the mechanisms by which TP53INP2 participates in the response to TRAIL were analyzed by Western blot, ubiquitination, coimmunoprecipitation and immunofluorescence assays. Finally, the effect of TRAIL alone or in combination with the BCL-2 inhibitor venetoclax (VEN) on cell survival was explored using colony formation and FCM assays, and the effect on leukemogenesis was further investigated in a patient-derived xenograft (PDX) mouse model.Results AML cells with high TP53INP2 expression were more sensitive to TRAIL in vitro and in vivo. Gain- and loss-of-function studies demonstrated that TP53INP2 significantly enhanced TRAIL-induced apoptosis, especially in AML cells with nucleophosmin 1 (NPM1) mutations. Mechanistically, cytoplasmic TP53INP2 maintained by mutant NPM1 functions as a scaffold bridging the ubiquitin ligase TRAF6 to caspase-8 (CASP 8), thereby promoting the ubiquitination and activation of the CASP 8 pathway. More importantly, simultaneously stimulating extrinsic and intrinsic apoptosis signaling pathways with TRAIL and VEN showed strong synergistic antileukemic activity in AML cells with high levels of TP53INP2.Conclusion Our findings revealed that TP53INP2 is a predictor of responsiveness to TRAIL treatment and supported a potentially individualized therapeutic strategy for TP53INP2-positive AML patients.

基金机构：National Natural Science Foundation of China [82072353, 82102377]; Natural Science Foundation of CQ CSTC [cstc2021jcyj-msxmX0363]; Graduate Scientific Research and Innovation Project of Chongqing [CYS20204]; Outstanding Postgraduate Fund of Chongqing Medical University [BJRC202210]

基金资助正文：This work was supported by National Natural Science Foundation of China (Grant No: 82072353; 82102377); Natural Science Foundation of CQ CSTC (Grant No: cstc2021jcyj-msxmX0363); Graduate Scientific Research and Innovation Project of Chongqing (Grant No: CYS20204); Outstanding Postgraduate Fund of Chongqing Medical University (Grant No: BJRC202210).