Liu, Minxia and Wang, Yinyin and Miettinen, Juho J. and Kumari, Romika and Majumder, Muntasir Mamun and Tierney, Ciara and Bazou, Despina and Parsons, Alun and Suvela, Minna and Lievonen, Juha and Silvennoinen, Raija and Anttila, Pekka and Dowling, Paul and O’Gorman, Peter and Tang, Jing and Heckman, Caroline A. (2021) S100 Calcium Binding Protein Family Members Associate With Poor Patient Outcome and Response to Proteasome Inhibition in Multiple Myeloma. Frontiers in Cell and Developmental Biology, 9. ISSN 2296-634X

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Abstract

Despite several new therapeutic options, multiple myeloma (MM) patients experience multiple relapses and inevitably become refractory to treatment. Insights into drug resistance mechanisms may lead to the development of novel treatment strategies. The S100 family is comprised of 21 calcium binding protein members with 17 S100 genes located in the 1q21 region, which is commonly amplified in MM. Dysregulated expression of S100 family members is associated with tumor initiation, progression and inflammation. However, the relationship between the S100 family and MM pathogenesis and drug response is unknown. In this study, the roles of S100 members were systematically studied at the copy number, transcriptional and protein level with patients’ survival and drug response. Copy number analysis revealed a predominant pattern of gains occurring in S100 genes clustering in the 1q21 locus. In general, gains of genes encoding S100 family members associated with worse patient survival. However, S100 gene copy number and S100 gene expression did not necessarily correlate, and high expression of S100A4 associated with poor patient survival. Furthermore, integrated analysis of S100 gene expression and ex vivo drug sensitivity data showed significant negative correlation between expression of S100 family members (S100A8,S100A9, and S100A12) and sensitivity to some drugs used in current MM treatment, including proteasome inhibitors (bortezomib, carfilzomib, and ixazomib) and histone deacetylase inhibitor panobinostat. Combined proteomic and pharmacological data exhibited significant negative association of S100 members (S100A4, S100A8, and S100A9) with proteasome inhibitors and panobinostat. Clinically, the higher expression of S100A4 and S100A10 were significantly linked to shorter progression free survival in patients receiving carfilzomib-based therapy. The results indicate an association and highlight the potential functional importance of S100 members on chromosome 1q21 in the development of MM and resistance to established myeloma drugs, including proteasome inhibitors

Item Type:	Article
Additional Information:	Liu M, Wang Y, Miettinen JJ, Kumari R, Majumder MM, Tierney C, Bazou D, Parsons A, Suvela M, Lievonen J, Silvennoinen R, Anttila P, Dowling P, O’Gorman P, Tang J and Heckman CA (2021) S100 Calcium Binding Protein Family Members Associate With Poor Patient Outcome and Response to Proteasome Inhibition in Multiple Myeloma. Front. Cell Dev. Biol. 9:723016. doi: 10.3389/fcell.2021.723016
Keywords:	multiple myeloma; S100 protein family; drug resistance; proteasome inhibitors; panobinostat
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Human Health Institute
Item ID:	17271
Identification Number:	https://doi.org/10.3389/fcell.2021.723016
Depositing User:	Paul Dowling
Date Deposited:	01 Jun 2023 14:29
Journal or Publication Title:	Frontiers in Cell and Developmental Biology
Publisher:	Frontiers
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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