Lymphocyte cytosolic protein 1 (LCP1) is a novel TRAF3 dysregulation biomarker with potential prognostic value in multip
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ORIGINAL RESEARCH PAPER
Lymphocyte cytosolic protein 1 (LCP1) is a novel TRAF3 dysregulation biomarker with potential prognostic value in multiple myeloma Eun Myoung Shin1 · Sultan Abda Neja10 · Kerem Fidan1,9 · Joelle Yi Heng Chua1 · Tae‑Hoon Chung2 · Nicolas Bertin3 · Vinay Tergaonkar1,4,7,8 · Wee‑Joo Chng2,5,6 · Melissa Gaik‑Ming Ooi5,6 Received: 27 March 2020 / Revised: 15 May 2020 / Accepted: 16 May 2020 © Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare 2020
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 NIKdriven 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. Keywords Lymphocyte cellular protein 1 (LCP1) · NF-κB inducing kinase (NIK) · TNF receptor associated factor 3 (TRAF3) · Non-canonical NF-κB · Multiple myeloma
Introduction Eun Myoung Shin and Sultan Abda Neja shared first authorship. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s42764-020-00014-x) contains supplementary material, which is available to authorized users. * Melissa Gaik‑Ming Ooi [email protected] 1
Multiple myeloma (MM) is a malignancy of the antibodyproducing plasma cells that accumulate in the bone marrow. It is the 2nd most common hematopoietic malignancy, comprising approximately 1% of all cancers, 10% 6
Department of Hematology‑Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore 119074, Singapore
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Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia
Laboratory of NFκB Signaling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore
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Cancer Science Institute of Singapore, Singapore 117599, Singapore
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3
Genome Institute of Singapore, A*STAR, Singapore 138672, Singapore
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