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

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

doi:10.1038/s41467-021-25664-7

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.

Highlights

Acute myeloid leukemia (AML) remains incurable, largely due to its resistance to conventional treatments
We identify an important role for the ubiquitin ligase RING finger protein 5 (RNF5) in AML and demonstrate how RNF5 contributes to this form of leukemia
Our studies establish a function for RNF5 beyond its previously characterized activity in ER-associated degradation (ERAD) and proteostasis[6,30] and reveal mechanisms underlying its regulation of gene expression programs governing AML development and response to histone deacetylase (HDAC) inhibitors

Summary

Introduction

Acute myeloid leukemia (AML) remains incurable, largely due to its resistance to conventional treatments. 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. The retinoblastoma binding protein 4 (RBBP4) is a component of multi-protein complexes that function in nucleosome assembly and histone modifications, modulate gene transcription, and regulate the cell cycle and proliferation[15]. Such complexes include the nucleosome remodeling and deacetylase (NuRD) complex, polycomb repressor complex 2 (PRC2), and switch independent 3 A (SIN3A)[15,16]. Our data suggest that targeting RNF5 and HDAC pathways represents a therapeutic modality for AML and that RNF5 or RBBP4 abundance could serve as a prognostic marker and means to stratify patients for treatment with HDAC inhibitors

Methods

Results

Conclusion