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 BrownKristiina Vuori, Michael Jackson, Eytan Ruppin, Aniruddha J. Deshpande, Ze’ev A. Ronai

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number5397
JournalNature Communications
Issue number1
StatePublished - 13 Sep 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology


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