Yang Wanfang, Xie Juan, Hou Ruixia, Chen Xiuhua, Xu Zhifang, Tan Yanhong, Ren Fanggang, Zhang Yaofang, Xu Jing, Chang Jianmei, Wang Hongwei
Institute of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China; Shanxi University of Chinese Medicine, Jinzhong, China.
Institute of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China.
Leuk Res. 2020 Mar 19;92:106351. doi: 10.1016/j.leukres.2020.106351.
Most patients with acute myeloid leukemia (AML) achieve complete remission (CR) after induction chemotherapy, however, in some patients, the disease subsequently relapses and may lead to death. Leukemia stem cells (LSC) have been identified as the main cause for recurrence. Increased aldehyde dehydrogenase (ALDH) activity in a variety of cancer stem cells prevents effective action of chemotherapeutic drugs. In this study, we found that approximately 50.7% of AML patients had ALDH, and the presence of ALDH stem cells was associated with poor cytogenetic prognosis. Lentiviral vector transduced ALDH leukemia cell lines are insensitive to the conventional chemotherapy drug cytarabine, and inhibition of ALDH activity by disulfiram (DSF) can increase the sensitivity of ALDH leukemia cells to cytarabine. Unlike traditional chemotherapy drugs, DSF is not toxic to healthy umbilical cord blood stem cells. An ALDH leukemia cell xenograft model was established using immunodeficient mice to mimic the disease environment, and DSF and cytarabine were found to eliminate the ALDH leukemia cells in transplanted mice while not affecting the healthy blood cells of mice. These findings suggest that DSF may have therapeutic potential by inhibiting ALDH activity and thereby increasing chemosensitivity.
大多数急性髓系白血病（AML）患者在诱导化疗后可实现完全缓解（CR），然而，部分患者疾病随后会复发并可能导致死亡。白血病干细胞（LSC）已被确定为复发的主要原因。多种癌症干细胞中醛脱氢酶（ALDH）活性增加会妨碍化疗药物发挥有效作用。在本研究中，我们发现约50.7%的AML患者存在ALDH，且ALDH干细胞的存在与细胞遗传学预后不良相关。慢病毒载体转导的ALDH白血病细胞系对传统化疗药物阿糖胞苷不敏感，而双硫仑（DSF）抑制ALDH活性可增加ALDH白血病细胞对阿糖胞苷的敏感性。与传统化疗药物不同，DSF对健康脐带血干细胞无毒。利用免疫缺陷小鼠建立了ALDH白血病细胞异种移植模型以模拟疾病环境，结果发现DSF和阿糖胞苷可清除移植小鼠体内的ALDH白血病细胞，同时不影响小鼠的健康血细胞。这些发现表明，DSF可能通过抑制ALDH活性从而增加化疗敏感性而具有治疗潜力。
