Costello Régis, Dancik Garrett M, Dubiau Anaïs, Madaci Lamia, Vlahopoulos Spiros
APHM, Hematology and Cellular Therapy Department, Conception Hospital, 13005 Marseille, France.
TAGC-Theories and Approaches of Genomic Complexity, INSERM, UMR1090, Parc Scientifique de Luminy, Aix Marseille University, 13009 Marseille, France.
Cells. 2025 Jul 7;14(13):1038. doi: 10.3390/cells14131038.
In acute myeloid leukemia (AML) it is important to elucidate the biological events that lead from remission to relapse, which have a high probability of leading to an adverse disease outcome. The cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1A1) is underexpressed in AML cells when compared to healthy cells, both at the RNA level and at the protein level, and at least in the former, both in the bone marrow and in peripheral blood. Nonetheless, ALDH1A1/ALDH1A2 activity increases in AML cells during disease relapse and is higher in adverse prognosis AML in comparison with favorable prognosis AML. Furthermore, especially in relapsed AML and in unfavorable AML, AML cells rich in ALDH1A1 can contain high levels of reactive oxygen species (ROS), in parallel with high ALDH1A1/2 activity. This metabolic feature is clearly incompatible with normal stem cells. The term "stem-like" therefore is useful to coin malignant cells with a variety of genetic makeups, metabolic programming and biomarkers that converge in the function of survival of clones sufficient to sustain, spread and re-establish neoplastic disease. Therefore, AML "stem-like" cells survive cancer treatment that eradicates other malignant cell clones. This fact differentiates AML "stem-like" cells from normal stem and progenitor cells that function in tissue regeneration as part of a distinct hierarchical order of cell phenotypes. The ODYSSEY clinical trial is a Phase I/II study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABD-3001, a novel therapeutic agent, in patients with AML who have relapsed or are refractory to standard treatments. In this context, ABD-3001 is used as an inhibitor of cytosolic ALDH1 enzymes, such as ALDH1A1 and ALDH1A2.
在急性髓系白血病（AML）中，阐明从缓解到复发的生物学事件很重要，因为这些事件极有可能导致不良的疾病结局。与健康细胞相比，癌症干细胞标志物醛脱氢酶1（ALDH1A1）在AML细胞中的RNA水平和蛋白质水平均低表达，至少在骨髓和外周血中的前者是这样。尽管如此，在疾病复发期间，AML细胞中的ALDH1A1/ALDH1A2活性会增加，与预后良好的AML相比，预后不良的AML中该活性更高。此外，尤其是在复发的AML和预后不良的AML中，富含ALDH1A1的AML细胞可含有高水平的活性氧（ROS），同时伴有高ALDH1A1/2活性。这种代谢特征显然与正常干细胞不相容。因此，“干细胞样”一词有助于描述具有多种基因组成、代谢程序和生物标志物的恶性细胞，这些细胞在足以维持、扩散和重建肿瘤疾病的克隆存活功能方面具有共同特征。因此，AML“干细胞样”细胞能在根除其他恶性细胞克隆的癌症治疗中存活下来。这一事实将AML“干细胞样”细胞与正常干细胞和祖细胞区分开来，正常干细胞和祖细胞在组织再生中发挥作用，是细胞表型独特层次结构的一部分。ODYSSEY临床试验是一项I/II期研究，旨在评估新型治疗药物ABD-3001在复发或对标准治疗难治的AML患者中的安全性、耐受性、药代动力学和药效学。在这种情况下，ABD-3001用作胞质ALDH1酶（如ALDH1A1和ALDH1A2）的抑制剂。
