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

    Cancer Cell. 2020 Feb 10;37(2):200-215.e5. doi: 10.1016/j.ccell.2020.01.001.
    • PMID: 32049046
    • PMCID: PMC7321798
    • DOI: 10.1016/j.ccell.2020.01.001

    Abstract

    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.

    Keywords: Aurora B kinase; FBXW7; MYC; T-ALL; patient-derived xenograft; phosphorylation; protein stability; zebrafish T-ALL model.

    Publication types

    • Research Support, N.I.H., Extramural
    • Research Support, Non-U.S. Gov't

    MeSH terms

    • Animals
    • Aurora Kinase A / genetics
    • Aurora Kinase A / immunology
    • Aurora Kinase B / immunology
    • Aurora Kinase B / metabolism*
    • Cell Line, Tumor
    • F-Box-WD Repeat-Containing Protein 7 / immunology
    • Humans
    • Mice
    • Phosphorylation
    • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
    • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / immunology*
    • Protein Kinase Inhibitors / pharmacology
    • T-Lymphocytes / drug effects
    • T-Lymphocytes / immunology*
    • Transcriptional Activation / drug effects
    • Transcriptional Activation / immunology
    • Zebrafish

    Substances

    • F-Box-WD Repeat-Containing Protein 7
    • FBXW7 protein, human
    • Protein Kinase Inhibitors
    • AURKB protein, human
    • Aurkb protein, mouse
    • Aurora Kinase A
    • Aurora Kinase B