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Khateb, A.* ; Deshpande, A.* ; Feng, Y.* ; Finlay, D.* ; Lee, J.S.* ; Lazar, I.* ; Fabre, B.* ; Li, Y.* ; Fujita, Y.* ; Zhang, T.* ; Yin, J.* ; Pass, I.* ; Livneh, I.* ; Jeremias, I. ; Burian, C.* ; Mason, J.R.* ; Almog, R.* ; Horesh, N.* ; Ofran, Y.* ; Brown, K.* ; Vuori, K.* ; Jackson, M.* ; Ruppin, E.* ; Deshpande, A.J.* ; Ronai, Z.A.*

The ubiquitin ligase RNF5 determines acute myeloid leukemia growth and susceptibility to histone deacetylase inhibitors.

Nat. Commun. 12:5397 (2021)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Acute myeloid leukemia (AML) remains incurable, largely due to its resistance to conventional treatments. Here, we find that increased abundance of the ubiquitin ligase RNF5 contributes to AML development and survival. High RNF5 expression in AML patient specimens correlates with poor prognosis. RNF5 inhibition decreases AML cell growth in culture, in patient-derived xenograft (PDX) samples and in vivo, and delays development of MLL-AF9–driven leukemogenesis in mice, prolonging their survival. RNF5 inhibition causes transcriptional changes that overlap with those seen upon histone deacetylase (HDAC)1 inhibition. RNF5 induces the formation of K29 ubiquitin chains on the histone-binding protein RBBP4, promoting its recruitment to and subsequent epigenetic regulation of genes involved in AML maintenance. Correspondingly, RNF5 or RBBP4 knockdown enhances AML cell sensitivity to HDAC inhibitors. Notably, low expression of both RNF5 and HDAC coincides with a favorable prognosis. Our studies identify an ERAD-independent role for RNF5, demonstrating that its control of RBBP4 constitutes an epigenetic pathway that drives AML, and highlight RNF5/RBBP4 as markers useful to stratify patients for treatment with HDAC inhibitors.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Reticulum-associated Degradation; Apoptosis; Binding; Identification; Expression; Prognosis; Proteins; Phase-1; Complex; Cells
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 12, Issue: 1, Pages: , Article Number: 5397 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
POF-Topic(s) 30204 - Cell Programming and Repair
Research field(s) Stem Cell and Neuroscience
PSP Element(s) G-506600-001
Grants U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
DOI 10.1038/s41467-021-25664-7
WOS ID WOS:000700373400011
Scopus ID 85114876306
PubMed ID 34518534
Erfassungsdatum 2021-10-15
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