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

Ali Khateb, Anagha Deshpande, Yongmei Feng, Darren Finlay, Joo Sang Lee, Ikrame Lazar, Bertrand Fabre, Yan Li, Yu Fujita, Tongwu Zhang, Jun Yin, Ian Pass, Ido Livneh, Irmela Jeremias, Carol Burian, James R. Mason, Ronit Almog, Nurit Horesh, Yishai Ofran, Kevin Brown, Kristiina Vuori, Michael Jackson, Eytan Ruppin, Aniruddha J. Deshpande and Ze’ev A. Ronai ()
Additional contact information
Ali Khateb: Technion Israel Institute of Technology
Anagha Deshpande: Sanford Burnham Prebys Medical Discovery Institute
Yongmei Feng: Sanford Burnham Prebys Medical Discovery Institute
Darren Finlay: Sanford Burnham Prebys Medical Discovery Institute
Joo Sang Lee: National Cancer Institute, National Institute of Health
Ikrame Lazar: Technion Israel Institute of Technology
Bertrand Fabre: Technion Israel Institute of Technology
Yan Li: Sanford Burnham Prebys Medical Discovery Institute
Yu Fujita: Sanford Burnham Prebys Medical Discovery Institute
Tongwu Zhang: National Cancer Institute
Jun Yin: Sanford Burnham Prebys Medical Discovery Institute
Ian Pass: Sanford Burnham Prebys Medical Discovery Institute
Ido Livneh: Technion Israel Institute of Technology
Irmela Jeremias: German Center for Environmental Health
Carol Burian: Scripps MD Anderson Cancer Center
James R. Mason: Scripps MD Anderson Cancer Center
Ronit Almog: Rambam Health Care Campus, Epidemiology Department and Biobank
Nurit Horesh: Hematology and Bone marrow Transplantation Department
Yishai Ofran: Technion Israel Institute of Technology
Kevin Brown: National Cancer Institute
Kristiina Vuori: Sanford Burnham Prebys Medical Discovery Institute
Michael Jackson: Sanford Burnham Prebys Medical Discovery Institute
Eytan Ruppin: National Cancer Institute, National Institute of Health
Aniruddha J. Deshpande: Sanford Burnham Prebys Medical Discovery Institute
Ze’ev A. Ronai: Sanford Burnham Prebys Medical Discovery Institute

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25664-7

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DOI: 10.1038/s41467-021-25664-7

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