Direct Phosphorylation and Stabilization of MYC by Aurora B Kinase Promote T-cell Leukemogenesis
Direct Phosphorylation and Stabilization of MYC by Aurora B Kinase Promote T-cell Leukemogenesis
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Aurora B 激酶直接磷酸化和稳定 MYC，促进 T 细胞白血病发生。
DOI：
10.1016/j.ccell.2020.01.001
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发表时间：
2020-02-10
期刊：
影响因子：
50.3
通讯作者：
Liu, Hudan
中科院分区：
文献类型：
--
作者：
Jiang, Jue;Wang, Jingchao;Liu, Hudan
MYC的去调节在T细胞急性淋巴细胞白血病(T-ALL)中起重要作用，但其去调节的机制仍不清楚。在这里，我们确定了Aurora B激酶(AURKB)和MYC之间相互激活的分子机制。AURKB直接在丝氨酸67处磷酸化MYC，对抗GSK3b指导的苏氨酸58磷酸化和随后FBXW7介导的蛋白酶体降解。稳定的MYC与T细胞急性淋巴细胞白血病1(TAL1)结合，直接激活AURKB转录，构成一个正前馈环，加强MYC调节的致癌程序。因此，AURKB的抑制剂诱导显著的MYC降解伴随着强劲的白血病细胞死亡。这些发现揭示了T细胞白血病发生背后的AURKB-MYC调节回路，并为通过AURKB抑制治疗靶向致癌MYC提供了理论基础。
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 GSK3b-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.