Direct Phosphorylation and Stabilization of MYC by Aurora B Kinase Promote T-cell Leukemogenesis.

Cancer cell 2020 Feb 10

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Deregulation of MYC plays an essential role in T cell acute lymphoblastic leukemia (T-ALL), yet the mechanisms underlying its deregulation remain elusive. Herein, we identify a molecular mechanism responsible for reciprocal activation between Aurora B kinase (AURKB) and MYC. AURKB directly phosphorylates MYC at serine 67, counteracting GSK3β-directed threonine 58 phosphorylation and subsequent FBXW7-mediated proteasomal degradation. Stabilized MYC, in concert with T cell acute lymphoblastic leukemia 1 (TAL1), directly activates AURKB transcription, constituting a positive feedforward loop that reinforces MYC-regulated oncogenic programs. Therefore, inhibitors of AURKB induce prominent MYC degradation concomitant with robust leukemia cell death. These findings reveal an AURKB-MYC regulatory circuit that underlies T cell leukemogenesis, and provide a rationale for therapeutic targeting of oncogenic MYC via AURKB inhibition. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

Jue Jiang, Jingchao Wang, Ming Yue, Xiaolian Cai, Tianci Wang, Chao Wu, Hexiu Su, Yanwu Wang, Meng Han, Yingchi Zhang, Xiaofan Zhu, Peng Jiang, Peng Li, Yonghua Sun, Wuhan Xiao, Hui Feng, Guoliang Qing, Hudan Liu. Direct Phosphorylation and Stabilization of MYC by Aurora B Kinase Promote T-cell Leukemogenesis. Cancer cell. 2020 Feb 10;37(2):200-215.e5