S100 Calcium Binding Protein Family Members Associate With Poor Patient Outcome and Response to Proteasome Inhibition in Multiple Myeloma.

Minxia Liu,Jing Tang,Caroline A Heckman,Paul Dowling,Minna Suvela,Yinyin Wang,Alun Parsons,Despina Bazou,Romika Kumari,Muntasir Mamun Majumder,Juha Lievonen,Pekka Anttila,Juho J Miettinen,Raija Silvennoinen,Ciara Tierney,Peter O’Gorman

doi:10.3389/fcell.2021.723016

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.

Highlights

Multiple myeloma (MM) is the second most common hematologic malignancy characterized by the expansion of clonal plasma cells
Correlation analysis of S100 gain with disease stage and 1q21 gain showed S100 gains were detected more frequently in RRMM samples than samples from newly diagnosed MM patients (NDMM) samples and co-occurred with 1q21 gain, indicating 1q21 gain is a major factor for S100 gain (Table 1)
Integrated analysis of copy number variation (CNV) and gene expression showed that only S100A13 had a significant positive correlation (r = 0.42) between copy number gains and gene expression levels in the FIMM dataset (Supplementary Figure 2), suggesting that other mechanisms regulate S100 expression

Summary

Introduction

Multiple myeloma (MM) is the second most common hematologic malignancy characterized by the expansion of clonal plasma cells. The advent of novel agents, such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), have markedly improved patient outcome (Fonseca et al, 2017). Investigations of the genes within the 1q21 region have provided some insight into the mechanisms that could contribute to the poor outcome of patients with this aberration. These include CKS1B (Shaughnessy, 2005), MCL1 (Samo et al, 2018), IL6R (Teoh et al, 2020), and ADAR (Teoh et al, 2020), all of which have been shown to promote MM progression. The influence of other 1q21 genes on MM pathogenesis and patient response to treatment is largely unknown

Objectives

Methods

Results

Discussion

Conclusion