文章：

抑制醛脱氢酶可根除白血病干细胞，同时保留正常祖细胞

Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors

原文发布日期：2016-09-09

DOI: 10.1038/bcj.2016.78

类型: Original Article

开放获取: 是

英文摘要：

The vast majority of patients with acute myeloid leukemia (AML) achieve complete remission (CR) after standard induction chemotherapy. However, the majority subsequently relapse and die of the disease. A leukemia stem cell (LSC) paradigm has been invoked to explain this failure of CR to reliably translate into cure. Indeed, LSCs are highly enriched in CD34+CD38− leukemic cells that exhibit positive aldehyde dehydrogenase activity (ALDH+) on flow cytometry, these LSCs are resistant to currently existing treatments in AML such as cytarabine and anthracycline that, at the cost of great toxicity on normal cells, are highly active against the leukemic bulk, but spare the LSCs responsible for relapse. To try to combat the LSC population selectively, a well-characterized ALDH inhibitor by the trivial name of dimethyl ampal thiolester (DIMATE) was assessed on sorted CD34+CD38− subpopulations from AML patients and healthy patients. ALDH activity and cell viability were monitored by flow cytometry. From enzyme kinetic studies DIMATE is an active enzyme-dependent, competitive, irreversible inhibitor of ALDH1. On cells in culture, DIMATE is a powerful inhibitor of ALDHs 1 and 3, has a major cytotoxic activity on human AML cell lines. Moreover, DIMATE is highly active against leukemic populations enriched in LSCs, but, unlike conventional chemotherapy, DIMATE is not toxic for healthy hematopoietic stem cells which retained, after treatment, their self-renewing and multi-lineage differentiation capacity in immunodeficient mice, xenografted with human leukemic cells. DIMATE eradicates specifically human AML cells and spares healthy mouse hematologic cells.

摘要翻译： 

绝大多数急性髓系白血病（AML）患者经标准诱导化疗后可获得完全缓解（CR），但其中多数患者会随后复发并死于该疾病。为解释这种完全缓解未能可靠转化为治愈的现象，学界提出了白血病干细胞（LSC）理论模型。事实上，LSC高度富集于具有流式细胞术检测阳性醛脱氢酶活性（ALDH+）的CD34+CD38−白血病细胞中。这些LSC对当前AML治疗方案（如阿糖胞苷和蒽环类药物）具有耐药性——现有疗法虽能强效杀伤白血病主体细胞，却以正常细胞承受巨大毒性为代价，同时漏过了导致复发的LSC。

为尝试特异性靶向LSC群体，研究人员采用通用名为二甲基氨酰胺硫酯（DIMATE）的明确表征ALDH抑制剂，对AML患者和健康供体的分选CD34+CD38−细胞亚群进行评估。通过流式细胞术监测ALDH活性与细胞活力。酶动力学研究表明，DIMATE是一种活性酶依赖性、竞争性、不可逆的ALDH1抑制剂。在培养细胞实验中，DIMATE能强力抑制ALDH1和ALDH3，并对人AML细胞系表现出显著细胞毒活性。

更重要的是，DIMATE对富集LSC的白血病细胞群体具有强效杀伤作用，且与传统化疗不同：DIMATE对健康造血干细胞无毒性，经其处理后的干细胞在免疫缺陷小鼠（移植人白血病细胞）体内仍保持自我更新和多向分化能力。DIMATE能特异性清除人AML细胞，同时保留健康小鼠造血细胞。

原文链接：

Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors