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Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen

1
Institute for Molecular Medicine Finland-FIMM, HiLIFE–Helsinki Institute of Life Science, iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00290 Helsinki, Finland
2
Stem Cell Research Unit, Biomedical Center, University of Iceland, 101 Reykjavik, Iceland
3
Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland
4
Department of Hematology, Mater Misericordiae University Hospital, D07 Dublin, Ireland
5
Department of Biology, Maynooth University, National University of Ireland, W23 F2H6 Maynooth, Co. Kildare, Ireland
6
Oncopeptides AB, 111 53 Stockholm, Sweden
*
Author to whom correspondence should be addressed.
These authors equally contributed to this work.
Academic Editor: Enrique M. Ocio
Cancers 2021, 13(7), 1527; https://doi.org/10.3390/cancers13071527
Received: 8 January 2021 / Revised: 15 March 2021 / Accepted: 20 March 2021 / Published: 26 March 2021
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma (MM))
The aims of this study were to investigate aminopeptidase expression in multiple myeloma and to identify the aminopeptidases responsible for the activation of the peptide–drug conjugate melflufen in multiple myeloma. We observed a differential expression of aminopeptidases between relapsed/refractory and newly diagnosed multiple myeloma patients. A higher expression of the aminopeptidase genes XPNPEP1, RNPEP, DPP3, and BLMH in multiple myeloma plasma cells was associated with shorter patient overall survival. The peptide–drug conjugate melflufen was particularly active towards plasma cells from relapsed/refractory multiple myeloma patients. Melflufen could be hydrolyzed to its active form by the aminopeptidases LAP3, LTA4H, RNPEP, and ANPEP, all of which are expressed in multiple myeloma. These results indicate critical roles for aminopeptidases in disease progression and the activity of melflufen in multiple myeloma.
Multiple myeloma (MM) is characterized by extensive immunoglobulin production leading to an excessive load on protein homeostasis in tumor cells. Aminopeptidases contribute to proteolysis by catalyzing the hydrolysis of amino acids from proteins or peptides and function downstream of the ubiquitin–proteasome pathway. Notably, aminopeptidases can be utilized in the delivery of antibody and peptide-conjugated drugs, such as melflufen, currently in clinical trials. We analyzed the expression of 39 aminopeptidase genes in MM samples from 122 patients treated at Finnish cancer centers and 892 patients from the CoMMpass database. Based on ranked abundance, LAP3, ERAP2, METAP2, TTP2, and DPP7 were highly expressed in MM. ERAP2, XPNPEP1, DPP3, RNPEP, and CTSV were differentially expressed between relapsed/refractory and newly diagnosed MM samples (p < 0.05). Sensitivity to melflufen was detected ex vivo in 11/15 MM patient samples, and high sensitivity was observed, especially in relapsed/refractory samples. Survival analysis revealed that high expression of XPNPEP1, RNPEP, DPP3, and BLMH (p < 0.05) was associated with shorter overall survival. Hydrolysis analysis demonstrated that melflufen is a substrate for aminopeptidases LAP3, LTA4H, RNPEP, and ANPEP. The sensitivity of MM cell lines to melflufen was reduced by aminopeptidase inhibitors. These results indicate critical roles of aminopeptidases in disease progression and the activity of melflufen in MM. View Full-Text
Keywords: multiple myeloma; aminopeptidase; gene expression; melflufen multiple myeloma; aminopeptidase; gene expression; melflufen
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MDPI and ACS Style

Miettinen, J.J.; Kumari, R.; Traustadottir, G.A.; Huppunen, M.-E.; Sergeev, P.; Majumder, M.M.; Schepsky, A.; Gudjonsson, T.; Lievonen, J.; Bazou, D.; Dowling, P.; O`Gorman, P.; Slipicevic, A.; Anttila, P.; Silvennoinen, R.; Nupponen, N.N.; Lehmann, F.; Heckman, C.A. Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen. Cancers 2021, 13, 1527. https://doi.org/10.3390/cancers13071527

AMA Style

Miettinen JJ, Kumari R, Traustadottir GA, Huppunen M-E, Sergeev P, Majumder MM, Schepsky A, Gudjonsson T, Lievonen J, Bazou D, Dowling P, O`Gorman P, Slipicevic A, Anttila P, Silvennoinen R, Nupponen NN, Lehmann F, Heckman CA. Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen. Cancers. 2021; 13(7):1527. https://doi.org/10.3390/cancers13071527

Chicago/Turabian Style

Miettinen, Juho J.; Kumari, Romika; Traustadottir, Gunnhildur A.; Huppunen, Maiju-Emilia; Sergeev, Philipp; Majumder, Muntasir M.; Schepsky, Alexander; Gudjonsson, Thorarinn; Lievonen, Juha; Bazou, Despina; Dowling, Paul; O`Gorman, Peter; Slipicevic, Ana; Anttila, Pekka; Silvennoinen, Raija; Nupponen, Nina N.; Lehmann, Fredrik; Heckman, Caroline A. 2021. "Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen" Cancers 13, no. 7: 1527. https://doi.org/10.3390/cancers13071527

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