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Lymphocyte cytosolic protein 1 (LCP1) is a novel TRAF3 dysregulation biomarker with potential prognostic value in multiple myeloma

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Abstract

Chromosomal rearrangement involving 14q32 region that results in TNF receptor associated factor 3 (TRAF3) dysfunctional mutation is the most frequent NF-κB pathway mutation in multiple myeloma (MM). Subsequent NF-κB inducing Kinase (NIK) stabilization plays a critical role in alternative NF-κB activation. However, disease progression resulting from TRAF3 dysregulation has not been well understood. In this study, we identified lymphocyte cellular protein 1 (LCP1) as a novel NIK-driven alternative NF-κB target in TRAF3 dysfunctional mutation using RNA-seq, ChIP-seq (RelA/p65 and p52 NF-κB) and other validation methods. LCP1 is exclusively activated in MM cells with TRAF3 loss-of-function mutation. In MM patients, higher LCP1 expression was significantly pronounced in poor prognosis groups such as 4p16 and MAF. CD138 negative MM patient cells showed elevated LCP1 expression and inhibition of LCP1 can sensitize proteasome inhibitor bortezomib in TRAF3 mutant MM cells in vitro. We report that LCP1 is a NIK-driven biomarker in TRAF3 dysfunctional MM and targeting LCP1 can provide a valuable therapeutic intervention in TRAF3 mutated MM.

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Acknowledgements

We thank Dr. Manikandan Lakshmanan, Dr. Chew Chen Li, Dr. Lee Sook Yee, Dr. Gireedhar Venkatachalam for their productive discussions and suggestions for the manuscript.

Funding

This study was funded by Singapore Ministry of Health, National Medical Research Council Grant NMRC/CNIG/1170/2017.

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Author notes

  1. Eun Myoung Shin and Sultan Abda Neja shared first authorship.

Authors and Affiliations

  1. Laboratory of NFκB Signaling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, 138673, Singapore

    Eun Myoung Shin, Kerem Fidan, Joelle Yi Heng Chua & Vinay Tergaonkar

  2. Cancer Science Institute of Singapore, Singapore, 117599, Singapore

    Tae-Hoon Chung & Wee-Joo Chng

  3. Genome Institute of Singapore, A*STAR, Singapore, 138672, Singapore

    Nicolas Bertin

  4. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, 117597, Singapore

    Vinay Tergaonkar

  5. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore

    Wee-Joo Chng & Melissa Gaik-Ming Ooi

  6. Department of Hematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore, 119074, Singapore

    Wee-Joo Chng & Melissa Gaik-Ming Ooi

  7. Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074, Singapore

    Vinay Tergaonkar

  8. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, 5000, Australia

    Vinay Tergaonkar

  9. Denome Technologies, Singapore, 138673, Singapore

    Kerem Fidan

  10. Hawassa University, Awasa, Ethiopia

    Sultan Abda Neja

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  1. Eun Myoung Shin
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  8. Wee-Joo Chng
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Contributions

EMS performed the majority of experiments, SAN prepared RNA-seq samples, THC, NB, KF, JYHC performed bioinformatics studies. VT, WJC and MO designed the study and EMS and MO drafted the manuscript.

Corresponding author

Correspondence to Melissa Gaik-Ming Ooi.

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The authors declare no conflicts of interests.

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Shin, E.M., Neja, S.A., Fidan, K. et al. Lymphocyte cytosolic protein 1 (LCP1) is a novel TRAF3 dysregulation biomarker with potential prognostic value in multiple myeloma. GENOME INSTAB. DIS. 1, 286–299 (2020). https://doi.org/10.1007/s42764-020-00014-x

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