Department of Chemistry and Biochemistry, University of Hull, Kingston upon Hull HU6 7RX, UK.
Hull York Medical School, University of Hull, Kingston upon Hull HU6 7RX, UK.
Int J Mol Sci. 2023 Jun 2;24(11):9667. doi: 10.3390/ijms24119667.
Acute myeloid leukaemia (AML) is characterized by impaired myeloid differentiation resulting in an accumulation of immature blasts in the bone marrow and peripheral blood. Although AML can occur at any age, the incidence peaks at age 65. The pathobiology of AML also varies with age with associated differences in incidence, as well as the frequency of cytogenetic change and somatic mutations. In addition, 5-year survival rates in paediatrics are 60-75% but fall to 5-15% in older AML patients. This systematic review aimed to determine whether the altered genes in AML affect the same molecular pathways, indifferent of patient age, and, therefore, whether patients could benefit from the repurposing drugs or the use of the same immunotherapeutic strategies across age boundaries to prevent relapse. Using a PICO framework and PRISMA-P checklist, relevant publications were identified using five literature databases and assessed against an inclusion criteria, leaving 36 articles, and 71 targets for therapy, for further analysis. QUADAS-2 was used to determine the risk of bias and perform a quality control step. We then priority-ranked the list of cancer antigens based on predefined and pre-weighted objective criteria as part of an analytical hierarchy process used for dealing with complex decisions. This organized the antigens according to their potential to act as targets for the immunotherapy of AML, a treatment that offers an opportunity to remove residual leukaemia cells at first remission and improve survival rates. It was found that 80% of the top 20 antigens identified in paediatric AML were also within the 20 highest scoring immunotherapy targets in adult AML. To analyse the relationships between the targets and their link to different molecular pathways, PANTHER and STRING analyses were performed on the 20 highest scoring immunotherapy targets for both adult and paediatric AML. There were many similarities in the PANTHER and STRING results, including the most prominent pathways being angiogenesis and inflammation mediated by chemokine and cytokine signalling pathways. The coincidence of targets suggests that the repurposing of immunotherapy drugs across age boundaries could benefit AML patients, especially when used in combination with conventional therapies. However, due to cost implications, we would recommend that efforts are focused on ways to target the highest scoring antigens, such as WT1, NRAS, IDH1 and TP53, although in the future other candidates may prove successful.
急性髓系白血病（AML）的特征是髓系分化受损，导致骨髓和外周血中不成熟的原始细胞堆积。虽然 AML 可发生于任何年龄，但发病高峰在 65 岁。AML 的病理生物学也随年龄而变化，其发病率、细胞遗传学改变和体细胞突变的频率都有所不同。此外，儿科 AML 的 5 年生存率为 60-75%，但老年 AML 患者的生存率降至 5-15%。本系统评价旨在确定 AML 中改变的基因是否影响相同的分子途径，而与患者年龄无关，因此，患者是否可以受益于药物再利用或使用相同的免疫治疗策略来预防复发，跨越年龄界限。使用 PICO 框架和 PRISMA-P 检查表，通过五个文献数据库检索相关出版物，并根据纳入标准进行评估，留下 36 篇文章和 71 个治疗靶点进行进一步分析。使用 QUADAS-2 确定偏倚风险并进行质量控制步骤。然后，我们根据预先定义和预先加权的客观标准对癌症抗原列表进行优先级排序，作为用于处理复杂决策的层次分析过程的一部分。这根据抗原作为 AML 免疫治疗的靶标潜力对其进行了组织，免疫治疗为初次缓解时去除残留白血病细胞并提高生存率提供了机会。结果发现，在儿科 AML 中确定的前 20 个抗原中有 80%也在成人 AML 中得分最高的 20 个免疫治疗靶标内。为了分析靶标之间的关系及其与不同分子途径的联系，对成人和儿科 AML 的 20 个最高评分免疫治疗靶标进行了 PANTHER 和 STRING 分析。PANTHER 和 STRING 结果有许多相似之处，包括最突出的途径是血管生成和由趋化因子和细胞因子信号通路介导的炎症。靶标之间的一致性表明，免疫治疗药物在年龄界限上的重新利用可能使 AML 患者受益，特别是与常规治疗联合使用时。但是，由于成本的影响，我们建议将精力集中在靶向得分最高的抗原的方法上，例如 WT1、NRAS、IDH1 和 TP53，尽管在未来，其他候选者可能会成功。
