Cover Image

HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia

HOXA9 is commonly upregulated in acute myeloid leukemia (AML), in which it confers a poor prognosis. Characterizing the protein interactome of endogenous HOXA9 in human AML, we identified a chromatin complex of HOXA9 with the nuclear matrix attachment protein SAFB. SAFB perturbation phenocopied HOXA...

Full description

Saved in:
Bibliographic Details
Main Authors: Agrawal-Singh, Shuchi (Author) , Bagri, Jaana (Author) , Giotopoulos, George (Author) , Azazi, Dhoyazan M. A. (Author) , Horton, Sarah J. (Author) , Lopez, Cecile K. (Author) , Anand, Shubha (Author) , Bach, Anne-Sophie (Author) , Stedham, Frances (Author) , Antrobus, Robin (Author) , Houghton, Jack W. (Author) , Vassiliou, George S. (Author) , Sasca, Daniel (Author) , Yun, Haiyang (Author) , Whetton, Anthony D. (Author) , Huntly, Brian J. P. (Author)
Format: Article (Journal)
Language:English
Published: 6 April 2023
In: Blood
Year: 2023, Volume: 141, Issue: 14, Pages: 1737-1754
ISSN:1528-0020
DOI:10.1182/blood.2022016528
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/blood.2022016528
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0006497122084944
Get full text
Author Notes:Shuchi Agrawal-Singh, Jaana Bagri, George Giotopoulos, Dhoyazan M.A. Azazi, Sarah J. Horton, Cecile K. Lopez, Shubha Anand, Anne-Sophie Bach, Frances Stedham, Robin Antrobus, Jack W. Houghton, George S. Vassiliou, Daniel Sasca, Haiyang Yun, Anthony D. Whetton, and Brian J.P. Huntly
Description
Summary:HOXA9 is commonly upregulated in acute myeloid leukemia (AML), in which it confers a poor prognosis. Characterizing the protein interactome of endogenous HOXA9 in human AML, we identified a chromatin complex of HOXA9 with the nuclear matrix attachment protein SAFB. SAFB perturbation phenocopied HOXA9 knockout to decrease AML proliferation, increase differentiation and apoptosis in vitro, and prolong survival in vivo. Integrated genomic, transcriptomic, and proteomic analyses further demonstrated that the HOXA9-SAFB (H9SB)-chromatin complex associates with nucleosome remodeling and histone deacetylase (NuRD) and HP1γ to repress the expression of factors associated with differentiation and apoptosis, including NOTCH1, CEBPδ, S100A8, and CDKN1A. Chemical or genetic perturbation of NuRD and HP1γ-associated catalytic activity also triggered differentiation, apoptosis, and the induction of these tumor-suppressive genes. Importantly, this mechanism is operative in other HOXA9-dependent AML genotypes. This mechanistic insight demonstrates the active HOXA9-dependent differentiation block as a potent mechanism of disease maintenance in AML that may be amenable to therapeutic intervention by targeting the H9SB interface and/or NuRD and HP1γ activity.
Item Description:Gesehen am 01.08.2023
Physical Description:Online Resource
ISSN:1528-0020
DOI:10.1182/blood.2022016528

Similar Items