Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors.
Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors.
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DOI：
10.1038/bcj.2016.78
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发表时间：
2016-09-09
影响因子：
12.8
通讯作者：
Costello RT
中科院分区：
文献类型：
--
作者：
Venton G;Pérez-Alea M;Baier C;Fournet G;Quash G;Labiad Y;Martin G;Sanderson F;Poullin P;Suchon P;Farnault L;Nguyen C;Brunet C;Ceylan I;Costello RT
绝大多数急性髓性白血病（AML）患者在标准诱导化疗后达到完全缓解（CR）。然而，大多数人随后复发并死于这种疾病。白血病干细胞（LSC）范例已被用来解释CR无法可靠地转化为治愈。事实上，LSC高度富集在CD34+CD38−白血病细胞中，这些细胞在流式细胞仪上显示出阳性醛脱氢酶活性（ALDH+），这些LSC对目前AML中现有的治疗方法具有抗性，例如阿糖胞苷和蒽环类药物，这些药物以对正常细胞的巨大毒性为代价，对白血病细胞具有高度活性，但不影响导致复发的LSC。为了尝试选择性地对抗LSC群体，在来自AML患者和健康患者的分选的CD34+CD38−亚群上评估了一种具有良好特征的ALDH抑制剂，其俗名为二甲基安帕硫醇酯（DIMATE）。通过流式细胞术监测ALDH活性和细胞活力。根据酶动力学研究，DIMATE是ALDH 1的活性酶依赖性、竞争性、不可逆抑制剂。在培养的细胞上，DIMATE是ALDH 1和3的强效抑制剂，对人AML细胞系具有主要的细胞毒性活性。此外，DIMATE对富含LSC的白血病群体具有高度活性，但与常规化疗不同，DIMATE对健康的造血干细胞没有毒性，这些造血干细胞在治疗后保留了它们在异种移植有人白血病细胞的免疫缺陷小鼠中的自我更新和多谱系分化能力。DIMATE特异性根除人类AML细胞，并保留健康小鼠血液细胞。
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.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
64.8
作者：
Prost, Stephane;Relouzat, Francis;Leboulch, Philippe
通讯作者：
Leboulch, Philippe
DOI：
10.1073/pnas.0603806103
发表时间：
2006-08-01
影响因子：
11.1
作者：
Chute, John P.;Muramoto, Garrett G.;McDonnell, Donald P.
通讯作者：
McDonnell, Donald P.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.4
作者：
Gal, H.;Amariglio, N.;Givol, D.
通讯作者：
Givol, D.