MUC1-C oncoprotein suppresses reactive oxygen species-induced terminal differentiation of acute myelogenous leukemia cells
MUC1-C oncoprotein suppresses reactive oxygen species-induced terminal differentiation of acute myelogenous leukemia cells
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DOI：
10.1182/blood-2010-10-296632
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发表时间：
2011-05-05
期刊：
影响因子：
20.3
通讯作者：
Kufe, Donald
中科院分区：
文献类型：
--
作者：
Yin, Li;Wu, Zekui;Kufe, Donald
急性髓性白血病（AML）细胞的特征在于无限的自我更新和经历终末分化的能力受损。MUC 1癌蛋白在AML细胞中异常表达，然而，没有证据表明MUC 1参与髓系白血病的发生。MUC 1-C亚基的细胞穿透肽抑制剂阻断其寡聚化，从而阻断致癌功能。目前的结果表明，用这些抑制剂治疗人MOLM-14和MV 4 -11 AML细胞与生长停滞、诱导晚期凋亡/坏死和自我更新能力丧失相关。从AML患者的原代原始细胞中获得了类似的结果。MUC 1-C的抑制与活性氧（ROS）的增加和谷胱甘肽的消耗有关。ROS的增加与沿着髓系造血细胞分化的诱导有关。在这方面，MUC 1-C的抑制与AML细胞系和原代母细胞中通过ROS依赖性机制诱导终末分化的髓样表型相关。这些发现表明MUC 1-C功能对AML细胞自我更新具有重要意义，并且MUC 1-C的抑制代表了诱导AML细胞终末分化的潜在治疗方法。（血。2011;117（18）：4863-4870）
Acute myeloid leukemia (AML) cells are characterized by unlimited self-renewal and an impaired capacity to undergo terminal differentiation. The MUC1 oncoprotein is aberrantly expressed in AML cells; however, there has been no evidence for involvement of MUC1 in myeloid leukemogenesis. Cell-penetrating peptide inhibitors of the MUC1-C subunit block its oligomerization and thereby oncogenic function. The present results demonstrate that treatment of human MOLM-14 and MV4-11 AML cells with these inhibitors is associated with arrest of growth, induction of late apoptosis/necrosis, and loss of self-renewal capacity. Similar results were obtained with primary blasts from patients with AML. Inhibition of MUC1-C was associated with increases in reactive oxygen species (ROS) and depletion of glutathione. Increases in ROS have been linked to induction of hematopoietic cell differentiation along the myeloid lineage. In this regard, inhibition of MUC1-C was associated with induction of a terminally differentiated myeloid phenotype in AML cell lines and primary blasts by an ROS-dependent mechanism. These findings indicate that MUC1-C function is of importance to AML cell self-renewal and that inhibition of MUC1-C represents a potential therapeutic approach to induce terminal differentiation of AML cells. (Blood. 2011;117(18):4863-4870)