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    Oligomeric self-association contributes to E2A-PBX1-mediated oncogenesis

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    Authors
    Lin, CH
    Wang, Z
    Duque-Afonso, J
    Wong, SH
    Demeter, J
    Loktev, AV
    Somervaille, Tim CP
    Jackson, PK
    Cleary, ML
    Affiliation
    Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA
    Issue Date
    2019
    
    Metadata
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    Abstract
    The PBX1 homeodomain transcription factor is converted by t(1;19) chromosomal translocations in acute leukemia into the chimeric E2A-PBX1 oncoprotein. Fusion with E2A confers potent transcriptional activation and constitutive nuclear localization, bypassing the need for dimerization with protein partners that normally stabilize and regulate import of PBX1 into the nucleus, but the mechanisms underlying its oncogenic activation are incompletely defined. We demonstrate here that E2A-PBX1 self-associates through the PBX1 PBC-B domain of the chimeric protein to form higher-order oligomers in t(1;19) human leukemia cells, and that this property is required for oncogenic activity. Structural and functional studies indicate that self-association facilitates the binding of E2A-PBX1 to DNA. Mutants unable to self-associate are transformation defective, however their oncogenic activity is rescued by the synthetic oligomerization domain of FKBP, which confers conditional transformation properties on E2A-PBX1. In contrast to self-association, PBX1 protein domains that mediate interactions with HOX DNA-binding partners are dispensable. These studies suggest that oligomeric self-association may compensate for the inability of monomeric E2A-PBX1 to stably bind DNA and circumvents protein interactions that otherwise modulate PBX1 stability, nuclear localization, DNA binding, and transcriptional activity. The unique dependence on self-association for E2A-PBX1 oncogenic activity suggests potential approaches for mechanism-based targeted therapies.
    Citation
    Lin CH, Wang Z, Duque-Afonso J, Wong SH, Demeter J, Loktev AV, et al. Oligomeric self-association contributes to E2A-PBX1-mediated oncogenesis. Sci Rep. 2019 Mar 20;9(1):4915.
    Journal
    Scientific Reports
    URI
    http://hdl.handle.net/10541/621739
    DOI
    10.1038/s41598-019-41393-w
    PubMed ID
    30894657
    Additional Links
    https://dx.doi.org/10.1038/s41598-019-41393-w
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41598-019-41393-w
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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