Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
Cancer Research Institute Ghent, Ghent, Belgium.
Pediatr Res. 2021 May;89(7):1695-1705. doi: 10.1038/s41390-020-01199-3. Epub 2020 Oct 17.
Still 30-40% of pediatric acute myeloid leukemia (pedAML) patients relapse. Delineation of the transcriptomic profile of leukemic subpopulations could aid in a better understanding of molecular biology and provide novel biomarkers.
Using microarray profiling and quantitative PCR validation, transcript expression was measured in leukemic stem cells (LSC, n = 24) and leukemic blasts (L-blast, n = 25) from pedAML patients in comparison to hematopoietic stem cells (HSCs, n = 19) and control myeloblasts (C-blast, n = 20) sorted from healthy subjects. Gene set enrichment analysis was performed to identify relevant gene set enrichment signatures, and functional protein associations were identified by STRING analysis.
Highly significantly overexpressed genes in LSC and L-blast were identified with a vast majority not studied in AML. CDKN1A, CFP, and CFD (LSC) and HOMER3, CTSA, and GADD45B (L-blast) represent potentially interesting biomarkers and therapeutic targets. Eleven LSC downregulated targets were identified that potentially qualify as tumor suppressor genes, with MYCT1, PBX1, and PTPRD of highest interest. Inflammatory and immune dysregulation appeared to be perturbed biological networks in LSC, whereas dysregulated metabolic profiles were observed in L-blast.
Our study illustrates the power of taking into account cell population heterogeneity and reveals novel targets eligible for functional evaluation and therapy in pedAML.
Novel transcriptional targets were discovered showing a significant differential expression in LSCs and blasts from pedAML patients compared to their normal counterparts from healthy controls. Deregulated pathways, including immune and metabolic dysregulation, were addressed for the first time in children, offering a deeper understanding of the molecular pathogenesis. These novel targets have the potential of acting as biomarkers for risk stratification, follow-up, and targeted therapy. Multiple LSC-downregulated targets endow tumor suppressor roles in other cancer entities, and further investigation whether hypomethylating therapy could result into LSC eradication in pedAML is warranted.
仍有 30-40%的儿科急性髓系白血病（pedAML）患者复发。白血病亚群的转录组谱描述有助于更好地了解分子生物学，并提供新的生物标志物。
使用微阵列分析和定量 PCR 验证，比较了来自 pedAML 患者的白血病干细胞（LSC，n=24）和白血病母细胞（L-blast，n=25）与来自健康受试者的造血干细胞（HSCs，n=19）和对照髓母细胞（C-blast，n=20）的转录表达。进行基因集富集分析以确定相关基因集富集特征，并通过 STRING 分析鉴定功能蛋白关联。
鉴定出在 LSC 和 L-blast 中高度过表达的基因，其中绝大多数在 AML 中未得到研究。CDKN1A、CFP 和 CFD（LSC）和 HOMER3、CTSA 和 GADD45B（L-blast）代表潜在的有意义的生物标志物和治疗靶点。鉴定出 11 个 LSC 下调靶点，这些靶点可能是肿瘤抑制基因，其中 MYCT1、PBX1 和 PTPRD 最受关注。在 LSC 中，炎症和免疫失调似乎是被扰乱的生物学网络，而在 L-blast 中观察到代谢失调。
我们的研究说明了考虑细胞群体异质性的力量，并揭示了在 pedAML 中具有功能评估和治疗潜力的新靶标。
在 pedAML 患者的 LSCs 和母细胞中发现了新的转录靶标，与来自健康对照的正常细胞相比，它们的表达差异显著。首次在儿童中研究了失调的途径，包括免疫和代谢失调，这为分子发病机制提供了更深入的了解。这些新的靶标有可能作为风险分层、随访和靶向治疗的生物标志物。多个 LSC 下调的靶标在其他癌症实体中赋予肿瘤抑制作用，并且进一步研究低甲基化治疗是否会导致 pedAML 中 LSC 消除是值得的。
