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

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http://hdl.handle.net/10138/330724

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Miettinen , J , Kumari , R , Traustadottir , G A , Huppunen , M-E A , 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 2021 , ' Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen ' , Cancers , vol. 13 , no. 7 , 1527 . https://doi.org/10.3390/cancers13071527

Title: Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen
Author: Miettinen, Juho; Kumari, Romika; Traustadottir, Gunnhildur Asta; Huppunen, Maiju-Emilia Anniina; 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
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Hematologian yksikkö
University of Helsinki, HUS Comprehensive Cancer Center
University of Helsinki, Department of Oncology
University of Helsinki, Institute for Molecular Medicine Finland
Date: 2021-04
Language: eng
Number of pages: 21
Belongs to series: Cancers
ISSN: 2072-6694
URI: http://hdl.handle.net/10138/330724
Abstract: 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.
Subject: 3122 Cancers
Multiple Myeloma
Translational Medical Research
1184 Genetics, developmental biology, physiology
Gene expression
1182 Biochemistry, cell and molecular biology
Aminopeptidases
Proteomics
Flow cytometry
318 Medical biotechnology
Drug sensitivity and resistance testing
multiple myeloma
aminopeptidase
gene expression
melflufen
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