HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia
File(s)
Published version
OA Location
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2023-04-06
Date Acceptance
2022-11-28
Citation
Blood, 2023, 141 (14), pp.1737-1754
ISSN
0006-4971
Publisher
American Society of Hematology (ASH Publications)
Start Page
1737
End Page
1754
Journal / Book Title
Blood
Volume
141
Issue
14
Copyright Statement
© 2023 by The American Society of Hematology. This research was originally published in Blood. 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, Brian J. P. Huntly; HOXA9 forms a repressive complex with nuclear matrix–associated protein SAFB to maintain acute myeloid leukemia. Blood 2023; 141 (14): 1737–1754. doi: https://doi.org/10.1182/blood.2022016528 © the American Society of Hematology.
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/36577137
PII: S0006-4971(22)08494-4
Subjects
ACTIVATION
BINDING-PROTEIN
CHAETOCIN
CLASSIFICATION
DYSREGULATION
GENE
Hematology
IDENTIFICATION
Life Sciences & Biomedicine
PHASE-SEPARATION
Science & Technology
TRANSCRIPTION
TRANSLOCATION
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2022-12-28