RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
探索铜稳态相关基因失调在急性髓系白血病中的预后意义及治疗意义的临床验证
英文原题：Exploring and clinical validation of prognostic significance and therapeutic implications of copper homeostasis-related gene dysregulation in acute myeloid leukemia.
查看英文原题
Exploring and clinical validation of prognostic significance and therapeutic implications of copper homeostasis-related gene dysregulation in acute myeloid leukemia.
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中文摘要
铜稳态相关基因（CHRGs）在急性髓系白血病（AML）中的模式和生物学功能仍不清楚。我们探索了CHRGs在AML中的模式和生物学功能。利用独立队列，包括TCGA-GTEx、GSE114868、GSE37642和临床样本，我们鉴定了826个共同差异表达基因。
具体而言，12个铜死亡相关基因（如ATP7A、ATP7B）在AML中上调，而17个铜增殖相关基因（如ATOX1、ATP7A）下调。
我们使用LASSO-Cox、Kaplan-Meier和Nomogram分析建立预后风险模型，有效地将AML患者分为高风险组和低风险组。亚组分析显示，高风险患者总生存期较差，并涉及脂肪酸代谢、凋亡和糖酵解。免疫浸润分析表明免疫细胞组成存在差异，低风险组中B细胞、细胞毒性T细胞和记忆T细胞显著增加，而高风险组中单核细胞和中性粒细胞增加。单细胞测序分析证实了关键CHRGs（如MAPK1和ATOX1）的表达特征，这些基因与T细胞、B细胞和NK细胞功能相关。药物敏感性分析提示了靶向铜稳态的潜在治疗药物，包括Bicalutamide和Sorafenib。PCR验证证实了AML细胞系中4个铜死亡相关基因（LIPT1、SLC31A1、GCSH和PDHA1）和9个铜增殖相关基因（ATOX1、CCS、CP、MAPK1、SOD1、COA6、PDK1、DBH和PDE3B）的差异表达。
重要的是，这些基因可作为患者分层和治疗的潜在生物标志物。总之，我们揭示了CHRGs在AML中的表达模式和生物学功能。所开发的风险模型为患者生存提供了预后意义，为CHRGs的调控特征和AML个性化治疗的潜在途径提供了有价值的信息。
展开英文摘要原文
The patterns and biological functions of copper homeostasis-related genes (CHRGs) in acute myeloid leukemia (AML) remain unclear.
We explored the patterns and biological functions of CHRGs in AML. Using independent cohorts, including TCGA-GTEx, GSE114868, GSE37642, and clinical samples, we identified 826 common differentially expressed genes. Specifically, 12 cuproptosis-related genes (e. g. , ATP7A, ATP7B) were upregulated, while 17 cuproplasia-associated genes (e. g. , ATOX1, ATP7A) were downregulated in AML.
We used LASSO-Cox, Kaplan-Meier, and Nomogram analyses to establish prognostic risk models, effectively stratifying patients with AML into high- and low-risk groups. Subgroup analysis revealed that high-risk patients exhibited poorer overall survival and involvement in fatty acid metabolism, apoptosis, and glycolysis. Immune infiltration analysis indicated differences in immune cell composition, with notable increases in B cells, cytotoxic T cells, and memory T cells in the low-risk group, and increased monocytes and neutrophils in the high-risk group.
Single-cell sequencing analysis corroborated the expression characteristics of critical CHRGs, such as MAPK1 and ATOX1, associated with the function of T, B, and NK cells. Drug sensitivity analysis suggested potential therapeutic agents targeting copper homeostasis, including Bicalutamide and Sorafenib. PCR validation confirmed the differential expression of 4 cuproptosis-related genes (LIPT1, SLC31A1, GCSH, and PDHA1) and 9 cuproplasia-associated genes (ATOX1, CCS, CP, MAPK1, SOD1, COA6, PDK1, DBH, and PDE3B) in AML cell line.
Importantly, these genes serve as potential biomarkers for patient stratification and treatment.
In conclusion, we shed light on the expression patterns and biological functions of CHRGs in AML. The developed risk models provided prognostic implications for patient survival, offering valuable information on the regulatory characteristics of CHRGs and potential avenues for personalized treatment in AML.
论文信息
- 作者
- Abulimiti M、Jia ZY、Wu Y、Yu J、Gong YH、Guan N、Xiong DQ、Ding N
- 第一作者单位
- School of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China.China
- 通讯作者单位
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China. JieW629@163.com.China
- 期刊
- Annals of hematology2024 Aug
- 原文标识
- PubMed 38879648 · DOI 10.1007/s00277-024-05841-6