3 years ago

Antitumor effects of blocking protein neddylation in T315I-BCR-ABL leukemia cells and leukemia stem cells.

Jingfeng Zhou, Yangqiu Li, Yuhong Lu, Jingxuan Pan, Juan Li, Yanli Jin, Chang Liu, Danian Nie, Xin Du
Imatinib (IM) 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 (LSCs) that lie at the root of IM-resistant recurrences. Based on 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 IM-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 CD34+ 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 IM resistance in CML.

Publisher URL: http://doi.org/10.1158/0008-5472.CAN-17-1733

DOI: 10.1158/0008-5472.CAN-17-1733

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