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RNF5 Regulation of RBBP4 Defines Acute Myeloid Leukemia Growth and Susceptibility to Histone Deacetylase Inhibitors

By Ali Khateb, Anagha Deshpande, Yongmei Feng, Joo Sang Lee, Ikrame Lazar, Bertrand Fabre, Yan Li, Darren Finlay, Yu Fujita, Tongwu Zhang, Jun Yin, Ian Pass, Ido Livneh, Carol Burian, James R Mason, Ronit Almog, Nurit Horesh, Yishai Ofran, Kevin Brown, Kristiina Vuori, Michael Jackson, Eytan Ruppin, Aniruddha J Deshpande, Ze'ev A Ronai

Posted 25 Oct 2020
bioRxiv DOI: 10.1101/2020.10.25.349241

Acute myeloid leukemia (AML) remains incurable, largely due to its resistance to conventional treatments. Here, we found that increased expression and abundance of the ubiquitin ligase RNF5 contributes to AML development and survival. High RNF5 expression in AML patients correlated with poor prognosis. RNF5 inhibition decreased AML cell growth in culture and in vivo, and blocked development of MLL AF9 driven leukemogenesis in mice, prolonging their survival. RNF5 inhibition led to transcriptional changes that overlapped with those seen upon HDAC1 inhibition. RNF5 induced the formation of K29 ubiquitin chains on the histone-binding protein RBBP4, promoting its recruitment and subsequent epigenetic regulation of genes involved in AML development and maintenance. Correspondingly, RNF5 or RBBP4 knockdown enhanced the sensitivity of AML cells to histone deacetylase (HDAC) inhibitors. Notably, low expression of RNF5 and HDAC coincided with a favorable prognosis. Our studies identified ERAD independent role for RNF5, demonstrating that its control of RBBP4 constitutes an epigenetic pathway that drives AML while highlighting RNF5 and RBBP4 as markers to stratify patients for treatment with HDAC inhibitors. ### Competing Interest Statement There are no competing interest that are relevant to the work presented in this manuscript. ZAR is co-founder and serves as scientific advisor to Pangea Therapeutics. All other authors declare no competing interests.

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