Antitumor Effects of Blocking Protein Neddylation in T315I-BCR-ABL Leukemia Cells and Leukemia Stem Cells
Antitumor Effects of Blocking Protein Neddylation in T315I-BCR-ABL Leukemia Cells and Leukemia Stem Cells
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阻断 T315I-BCR-ABL 白血病细胞和白血病干细胞中蛋白 neddylation 的抗肿瘤作用
DOI：
10.1158/0008-5472.can-17-1733
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发表时间：
2018-03-15
期刊：
影响因子：
11.2
通讯作者：
Pan, Jingxuan
中科院分区：
文献类型：
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作者：
Liu, Chang;Nie, Danian;Pan, Jingxuan
伊马替尼彻底改变了慢性粒细胞白血病 (CML) 的治疗，但耐药性和疾病复发仍然是一个挑战。在这项研究中，我们提出了一种基于阻断蛋白质neddylation的新策略，以解决BCR-ABL点突变和白血病干细胞（LSC）问题，这些突变是伊马替尼耐药复发的根源。基于 NEDD8 激活酶亚基 NAE1 在 CML 细胞中过度表达的发现，我们假设某些 neddylation 依赖性蛋白底物的功能可能针对伊马替尼耐药的 CML 细胞和 LSC 的治疗目的。为了支持这一假设，我们证明 NAE1 抑制剂 MLN4924 诱导具有野生型 p53 的大量 CML 细胞的 G2-M 期停滞和凋亡，无论 BCR-ABL 中的 T315I 突变状态如何。此外，MLN4924 通过 p27kip1 在细胞核中的积累，抑制 CML 小鼠中原代人 CML CD34thorn 细胞和 LSC 的存活和自我更新。值得注意的是，p27kip1 沉默减弱了 MLN4924 对患有 CML 的小鼠 LSC 维持的抑制作用。总而言之，我们的研究结果为靶向蛋白质neddylation作为一种新的治疗策略提供了临床前概念证明，以克服CML中突变和LSC衍生的伊马替尼耐药性。意义：这些发现强调了蛋白质neddylation的介质（一种蛋白质周转机制）作为针对伊马替尼耐药形式的慢性粒细胞白血病的可行治疗靶点。
Imatinib revolutionized the treatment of chronic myeloid leukemia (CML), but drug resistance and disease recurrence remain a challenge. In this study, we suggest a novel strategy based on blocking protein neddylation to address BCR-ABL point mutations and leukemia stem cells (LSC) that lie at the root of imatinib-resistant recurrences. On the basis of the finding that the NEDD8-activating enzyme subunit NAE1 is overexpressed in CML cells, we hypothesized that the function of certain neddylation-dependent protein substrates might be targeted to therapeutic ends in imatinib-resistant CML cells and LSCs. In support of this hypothesis, we demonstrated that the NAE1 inhibitor MLN4924 induced G2-M-phase arrest and apoptosis in bulk CML cells with wild-type p53, regardless of their T315I mutation status in BCR-ABL. Moreover, MLN4924 inhibited the survival and self-renewal of primary human CML CD34thorn cells and LSCs in CML-bearing mice via accumulation of p27kip1 in the nucleus. Notably, p27kip1 silencing attenuated the suppressive effect of MLN4924 on the maintenance of LSCs in CML-bearing mice. Taken together, our findings offer a preclinical proof of concept for targeting protein neddylation as a novel therapeutic strategy to override mutational and LSC-derived imatinib resistance in CML.Significance: These findings highlight a mediator of protein neddylation, a type of protein turnover mechanism, as a viable therapeutic target against imatinib-resistant forms of chronic myelogenous leukemia.