Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan, China.
Cancer Med. 2022 Sep;11(17):3364-3380. doi: 10.1002/cam4.4687. Epub 2022 Mar 30.
The immune response in the bone marrow microenvironment has implications for progression and prognosis in acute myeloid leukemia (AML). However, few immune-related biomarkers for AML prognosis and immunotherapy response have been identified. We aimed to establish a predictive gene signature and to explore the determinants of prognosis in AML.
Immune-related genes with clinical significance were screened by a weighted gene co-expression network analysis. Seven immune-related genes were used to establish a gene signature by a multivariate Cox regression analysis. Based on the signature, low- and high-risk groups were compared with respect to the immune microenvironment, immune checkpoints, pathway activities, and mutation frequencies. The tumor immune dysfunction and exclusion (TIDE) method was used to predict the response to immune checkpoint blockade (ICB) therapy. The Connectivity Map database was used to explore small-molecule drugs expected to treat high-risk populations.
A seven-gene prognostic signature was used to classify patients into high- and low-risk groups. Prognosis was poorer for patients in the former than in the latter. The high-risk group displayed higher levels of immune checkpoint molecules (LAG3, PD-1, CTLA4, PD-L2, and PD-L1), immune cell infiltration (dendritic cells, T helper 1, and gamma delta T), and somatic mutations (NPM1 and RUNX1). Moreover, hematopoietic stem cell/leukemia stem cell pathways were enriched in the high-risk phenotype. Compared with that in the low-risk group, the lower TIDE score for the high-risk group implied that this group is more likely to benefit from ICB therapy. Finally, some drugs (FLT3 inhibitors and BCL inhibitors) targeting the expression profiles associated with the high-risk group were generated using Connectivity Map.
The newly developed immune-related gene signature is an effective biomarker for predicting prognosis in AML and provides a basis, from an immunological perspective, for the development of comprehensive therapeutic strategies.
骨髓微环境中的免疫反应对急性髓系白血病（AML）的进展和预后有影响。然而，目前尚未发现用于 AML 预后和免疫治疗反应的免疫相关生物标志物。本研究旨在建立一个预测基因特征，并探讨 AML 预后的决定因素。
通过加权基因共表达网络分析筛选具有临床意义的免疫相关基因。通过多变量 Cox 回归分析，使用 7 个免疫相关基因建立基因特征。基于该特征，比较低危和高危组在免疫微环境、免疫检查点、通路活性和突变频率方面的差异。使用肿瘤免疫功能障碍和排斥（TIDE）方法预测免疫检查点阻断（ICB）治疗的反应。使用连接图谱数据库（Connectivity Map database）探索有望治疗高危人群的小分子药物。
一个七基因预后特征用于将患者分为高危和低危组。前者的预后较后者差。高危组的免疫检查点分子（LAG3、PD-1、CTLA4、PD-L2 和 PD-L1）、免疫细胞浸润（树突状细胞、辅助性 T 细胞 1 和γδT 细胞）和体细胞突变（NPM1 和 RUNX1）水平更高。此外，高危表型中富集了造血干细胞/白血病干细胞途径。与低危组相比，高危组的 TIDE 评分较低，提示该组更有可能从 ICB 治疗中获益。最后，使用连接图谱数据库生成了一些针对与高危组相关表达谱的药物（FLT3 抑制剂和 BCL 抑制剂）。
新开发的免疫相关基因特征是预测 AML 预后的有效生物标志物，从免疫学角度为制定综合治疗策略提供了依据。
