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; Ze’ev A. Ronai

doi:10.1038/s41467-021-25664-7

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 journal › Article › peer-review

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.

Original language	English
Article number	5397
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25664-7
State	Published - Dec 2021
Externally published	Yes

Bibliographical note

Funding Information:
We thank Drs. Yuval Shaked, Tsila Zuckerman, and Netanel Horowitz (Faculty of Medicine, Technion) for providing leukemic cell lines, and members of the Deshpande and Ronai labs for technical support and discussions. We thank SBP and Technion Core facilities for help along with the different phases of this study. We thank Nancy R. Gough (BioSerendipity, LLC) for editorial assistance. Z.A.R. gratefully acknowledges support from the National Cancer Institute grant (R35CA197465) and the Technion. A.K. was supported by a Faculty of Medicine fellowship at the Technion. Sanford Burnham Prebys Shared Resources are supported by an NCI Cancer Center Support Grant (P30 CA030199).

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

ASJC Scopus subject areas

Chemistry (all)
Biochemistry, Genetics and Molecular Biology (all)
Physics and Astronomy (all)

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10.1038/s41467-021-25664-7

Cite this

Khateb, A., Deshpande, A., Feng, Y., Finlay, D., Lee, J. S., Lazar, I., Fabre, B., Li, Y., Fujita, Y., Zhang, T., Yin, J., Pass, I., Livneh, I., Jeremias, I., Burian, C., Mason, J. R., Almog, R., Horesh, N., Ofran, Y., ... Ronai, Z. A. (2021). The ubiquitin ligase RNF5 determines acute myeloid leukemia growth and susceptibility to histone deacetylase inhibitors. Nature Communications, 12(1), [5397]. https://doi.org/10.1038/s41467-021-25664-7

@article{754cd989f4f54d8da3b2f7ad56892329,

title = "The ubiquitin ligase RNF5 determines acute myeloid leukemia growth and susceptibility to histone deacetylase inhibitors",

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.",

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

note = "Funding Information: We thank Drs. Yuval Shaked, Tsila Zuckerman, and Netanel Horowitz (Faculty of Medicine, Technion) for providing leukemic cell lines, and members of the Deshpande and Ronai labs for technical support and discussions. We thank SBP and Technion Core facilities for help along with the different phases of this study. We thank Nancy R. Gough (BioSerendipity, LLC) for editorial assistance. Z.A.R. gratefully acknowledges support from the National Cancer Institute grant (R35CA197465) and the Technion. A.K. was supported by a Faculty of Medicine fellowship at the Technion. Sanford Burnham Prebys Shared Resources are supported by an NCI Cancer Center Support Grant (P30 CA030199). Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-25664-7",

language = "English",

volume = "12",

journal = "Nature Communications",

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Khateb, A, Deshpande, A, Feng, Y, Finlay, D, Lee, JS, Lazar, I, Fabre, B, Li, Y, Fujita, Y, Zhang, T, Yin, J, Pass, I, Livneh, I, Jeremias, I, Burian, C, Mason, JR, Almog, R, Horesh, N, Ofran, Y, Brown, K, Vuori, K, Jackson, M, Ruppin, E, Deshpande, AJ & Ronai, ZA 2021, 'The ubiquitin ligase RNF5 determines acute myeloid leukemia growth and susceptibility to histone deacetylase inhibitors', Nature Communications, vol. 12, no. 1, 5397. https://doi.org/10.1038/s41467-021-25664-7

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 - Funding Information: We thank Drs. Yuval Shaked, Tsila Zuckerman, and Netanel Horowitz (Faculty of Medicine, Technion) for providing leukemic cell lines, and members of the Deshpande and Ronai labs for technical support and discussions. We thank SBP and Technion Core facilities for help along with the different phases of this study. We thank Nancy R. Gough (BioSerendipity, LLC) for editorial assistance. Z.A.R. gratefully acknowledges support from the National Cancer Institute grant (R35CA197465) and the Technion. A.K. was supported by a Faculty of Medicine fellowship at the Technion. Sanford Burnham Prebys Shared Resources are supported by an NCI Cancer Center Support Grant (P30 CA030199). Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

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.

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

Abstract

Bibliographical note

ASJC Scopus subject areas

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