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    HMG20B stabilizes association of LSD1 with GFI1 on chromatin to confer transcription repression and leukemia cell differentiation block

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    Authors
    Maiques-Diaz, Alba
    Nicosia, Luciano
    Basma, Naseer J
    Romero-Camarero, Isabel
    Camera, Francesco
    Spencer, Gary J
    Amaral, Fabio M R
    Simeoni, Fabrizio
    Wingelhofer, Bettina
    Williamson, Andrew J K
    Pierce, Andrew
    Whetton, A. D.
    Somervaille, Tim C P
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    Affiliation
    Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester Cancer Research Centre Building, 555 Wilmslow Road, Manchester, M20 4GJ, UK
    Issue Date
    2022
    
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    Abstract
    Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we applied mass spectrometry technologies. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is co-located on chromatin with GFI1 and LSD1 genome-wide; the strongest HMG20B binding co-locates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing LSD1 on chromatin at GFI1 binding sites. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukemia cell differentiation block.
    Citation
    Maiques-Diaz A, Nicosia L, Basma NJ, Romero-Camarero I, Camera F, Spencer GJ, et al. HMG20B stabilizes association of LSD1 with GFI1 on chromatin to confer transcription repression and leukemia cell differentiation block. Oncogene. 2022 Sep 28. PubMed PMID: 36171271. Epub 2022/09/29. eng.
    Journal
    Oncogene
    URI
    http://hdl.handle.net/10541/625693
    DOI
    10.1038/s41388-022-02471-y
    PubMed ID
    36171271
    Additional Links
    https://dx.doi.org/10.1038/s41388-022-02471-y
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41388-022-02471-y
    Scopus Count
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    All Paterson Institute for Cancer Research

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