Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Multiple myeloma, gammopathies

RFWD2 induces cellular proliferation and selective proteasome inhibitor resistance by mediating P27 ubiquitination in multiple myeloma

Leukemia volume 35, pages 1803–1807 (2021)Cite this article

Subjects

Proteasome inhibitors (PIs) contribute to the main armamentarium for treatment of multiple myeloma (MM) patients [1]. Currently, three PIs are approved for different patient populations including bortezomib (BTZ), carfilzomib (CFZ), and ixazomib (IXZ). Effective as single agents each in about one third of MM patients, most patients initially respond, but develop drug-resistance following the treatment [2]. Several potential explanations have been suggested, including mutations of the drug-target, i.e., the 26S proteasome subunit β5 [3], upregulation of the proteasome or subunits thereof, or involvement of endoplasmic reticulum stress pathways and bone marrow microenvironment [4,5,6]. In addition, our previous work described the roles of P21 and P27 [7], both important factor in the D-type cyclin disease of PI-resistance MM [8]. Based on these studies, we identified the gene constitutive photomorphogenic 1 (RFWD2, also known as COP1) located at the chromosomal position 1q25 as key regulator of P27, which potentially regulates proteasome-inhibitor resistance in MM. As an E3 ubiquitin ligase, RFWD2 has been shown to regulate the stability of P53, c-Jun, and FOXO1 [9], suggesting RFWD2 is engaged in several biological activities. In particular, RFWD2 is a negative regulator of P27, which contributes to CSN6-mediated P27 degradation in HCT116 and HEK-293T cells [10]. The aim of this study is to determine whether RFWD2 is associated to myeloma cellular proliferation, induces proteasome inhibitor resistance, and if it can be regarded as potential target in myeloma treatment.

Given that RFWD2 is located at chromosomal region 1q25, and 1q21 gain assessed by iFISH is associated with higher proliferation [13, 14], we investigated the interdependency of RFWD2-expression and chromosomal aberrations. We found that RFWD2-expression assessed by GEP and RNA-seq was significantly relevant to the presence of 1q21 (Supplementary Fig. S3A) and deletion of 13q14 (Supplementary Fig. S3B), but no difference was observed with the presence of del17p (Supplementary Fig. S3C). Moreover, these results were consolidated by GMMG-HD4 cohort analysis, in which RFWD2 was likewise increased in all high-risk groups, including ISS stage, GPI, UAMS70, RS, IFM15, EMC/SKY92, and MYC-activation Index [15] (Supplementary Fig. S4). Summarily, we hypothesize that RFWD2 is a high-risk gene in MM associated with cellular proliferation and part of the explanation for the adverse prognosis of gains of 1q21.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: RFWD2 is a high-risk gene in multiple myeloma.
Fig. 2: RFWD2 promotes MM cellular proliferation and drug-resistance by regulating P27 degradation.

References

  1. Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376:1311–20.

    Article  CAS  Google Scholar 

  2. Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754–66.

    Article  CAS  Google Scholar 

  3. Oerlemans R, Franke NE, Assaraf YG, Cloos J, van Zantwijk I, Berkers CR, et al. Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood. 2008;112:2489–99.

    Article  CAS  Google Scholar 

  4. Robak P, Drozdz I, Szemraj J, Robak T. Drug resistance in multiple myeloma. Cancer Treat Rev. 2018;70:199–208.

    Article  CAS  Google Scholar 

  5. Balsas P, Galan-Malo P, Marzo I, Naval J. Bortezomib resistance in a myeloma cell line is associated to PSMbeta5 overexpression and polyploidy. Leuk Res. 2012;36:212–8.

    Article  CAS  Google Scholar 

  6. Gandolfi S, Laubach JP, Hideshima T, Chauhan D, Anderson KC, Richardson PG. The proteasome and proteasome inhibitors in multiple myeloma. Cancer Metastasis Rev. 2017;36:561–84.

    Article  CAS  Google Scholar 

  7. Huang J, Zhou Y, Thomas GS, Gu Z, Yang Y, Xu H, et al. NEDD8 inhibition overcomes CKS1B-induced drug resistance by upregulation of p21 in multiple myeloma. Clin Cancer Res. 2015;21:5532–42.

    Article  CAS  Google Scholar 

  8. Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy J Jr. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005;106:296–303.

    Article  CAS  Google Scholar 

  9. Kato S, Ding J, Pisck E, Jhala U, Du K. COP1 functions as a FoxO1 ubiquitin E3 ligase to regulate FoxO1-mediated gene expression. J Biol Chem. 2008;283:35464–73.

    Article  CAS  Google Scholar 

  10. Choi HH, Guma S, Fang L, Phan L, Ivan C, Baggerly K, et al. Regulating the stability and localization of CDK inhibitor p27(Kip1) via CSN6-COP1 axis. Cell Cycle. 2015;14:2265–73.

    Article  CAS  Google Scholar 

  11. Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S, et al. The molecular classification of multiple myeloma. Blood. 2006;108:2020–8.

    Article  CAS  Google Scholar 

  12. Pernet CR, Wilcox RR, Rousselet GA. Robust correlation analyses: false positive and power validation using a new open source matlab toolbox. Front Psychol. 2013;3:606.

    Article  Google Scholar 

  13. Broyl A, Hose D, Lokhorst H, de Knegt Y, Peeters J, Jauch A, et al. Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients. Blood. 2010;116:2543–53.

    Article  CAS  Google Scholar 

  14. Zhan F, Colla S, Wu X, Chen B, Stewart JP, Kuehl WM, et al. CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms. Blood. 2007;109:4995–5001.

    Article  CAS  Google Scholar 

  15. Kuiper R, Broyl A, de Knegt Y, van Vliet MH, van Beers EH, van der Holt B, et al. A gene expression signature for high-risk multiple myeloma. Leukemia. 2012;26:2406–13.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by National Key Research and Development Program-precision medicine sub-program 2016YFC0905900 (to YY); National Natural Science Foundation of China 81970196 (to CG), 81670200 (to YY); The Priority Academic Program Development of Jiangsu Higher Education Institutions for Chinese Medicine.

Author information

Author notes

  1. These authors contributed equally: Chunyan Gu, Ting Lu

Authors and Affiliations

  1. The Third Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, China

    Chunyan Gu, Wang Wang, Rongfang Wei, Mengjie Guo, Rui Li, Li Qiao & Ye Yang

  2. School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China

    Chunyan Gu, Ting Lu, Wang Wang, Miaomiao Shao, Rongfang Wei, Mengjie Guo, Rui Li, Li Qiao, Ye Hu & Ye Yang

  3. Key Laboratory for Combination of Acupuncture and Chinese Materia Medica of Chinese Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, China

    Chunyan Gu, Wang Wang, Rongfang Wei, Mengjie Guo, Rui Li, Li Qiao & Ye Yang

  4. Internal Medicine, University of Iowa, Iowa City, IA, USA

    Fenghuang Zhan & Ye Yang

  5. Laboratory of Hematology and Immunology & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090, Jette, Belgium

    Anja Seckinger & Dirk Hose

Authors
  1. Chunyan Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ting Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miaomiao Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rongfang Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mengjie Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Li Qiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ye Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Fenghuang Zhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Anja Seckinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dirk Hose
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ye Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ye Yang.

Ethics declarations

Conflict of interest

No potential conflicts of interest were disclosed.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gu, C., Lu, T., Wang, W. et al. RFWD2 induces cellular proliferation and selective proteasome inhibitor resistance by mediating P27 ubiquitination in multiple myeloma. Leukemia 35, 1803–1807 (2021). https://doi.org/10.1038/s41375-020-01033-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-020-01033-z

This article is cited by

Search

Advanced search

Quick links