TY - JOUR
T1 - The ubiquitin ligase RNF5 determines acute myeloid leukemia growth and susceptibility to histone deacetylase inhibitors
AU - Khateb, Ali
AU - Deshpande, Anagha
AU - Feng, Yongmei
AU - Finlay, Darren
AU - Lee, Joo Sang
AU - Lazar, Ikrame
AU - Fabre, Bertrand
AU - Li, Yan
AU - Fujita, Yu
AU - Zhang, Tongwu
AU - Yin, Jun
AU - Pass, Ian
AU - Livneh, Ido
AU - Jeremias, Irmela
AU - Burian, Carol
AU - Mason, James R.
AU - Almog, Ronit
AU - Horesh, Nurit
AU - Ofran, Yishai
AU - Brown, Kevin
AU - Vuori, Kristiina
AU - Jackson, Michael
AU - Ruppin, Eytan
AU - Deshpande, Aniruddha J.
AU - Ronai, Ze’ev A.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/9/13
Y1 - 2021/9/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85114876306&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-25664-7
DO - 10.1038/s41467-021-25664-7
M3 - Article
C2 - 34518534
AN - SCOPUS:85114876306
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5397
ER -
