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Aminopeptidase expression in multiple myeloma associates with disease progression and sensitivity to melflufen

Aminopeptidase expression in multiple myeloma associates with disease progression and sensitivity to melflufen


Title: Aminopeptidase expression in multiple myeloma associates with disease progression and sensitivity to melflufen
Author: Miettinen, Juho J.
Kumari, Romika
Traustadóttir, Gunnhildur Ásta
Huppunen, Maiju Emilia
Sergeev, Philipp
Majumder, Muntasir M.
Schepsky, Alexander
Guðjónsson, Þórarinn
Lievonen, Juha
Bazou, Despina
... 8 more authors Show all authors
Date: 2021-03-26
Language: English
Scope:
University/Institute: University of Iceland
Landspitali - The National University Hospital of Iceland
Department: Faculty of Medicine
Clinical Laboratory Services, Diagnostics and Blood Bank
Series: Cancers; 13(7)
ISSN: 2072-6694
DOI: https://doi.org/10.3390/cancers13071527
Subject: Mergæxli; Ensím; Aminopeptidase; Gene expression; Melflufen; Multiple myeloma; Oncology; Cancer Research
URI: https://hdl.handle.net/20.500.11815/3233

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Citation:

Miettinen , J J , Kumari , R , Traustadóttir , G Á , Huppunen , M E , Sergeev , P , Majumder , M M , Schepsky , A , Guðjónsson , Þ , Lievonen , J , Bazou , D , Dowling , P , O‘gorman , P , Slipicevic , A , Anttila , P , Silvennoinen , R , Nupponen , N N , Lehmann , F & Heckman , C A 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

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.

Description:

Funding Information: Funding: This work has been supported by funding from Oncopeptides AB, Academy of Finland (grant 1320185), Cancer Society of Finland, and Sigrid Jusélius Foundation. Funding Information: Acknowledgments: These data were generated in part by the Multiple Myeloma Research Foundation Personalized Medicine Initiatives (https://research.themmrf.org and www.themmrf.org, accessed on 5 February 2018). This work has been supported by funding from Oncopeptides AB, Academy of Finland (grant 1320185), Cancer Society of Finland, and Sigrid Jusélius Foundation. The authors acknowledge use of the Q-Exactive quantitative mass spectrometer, funded under the Research Infrastructure Call 2012 by Science Foundation Ireland (SFI-12/RI/2346/3). The authors would like to thank Alun Parsons, Minna Suvela, the FIMM Sequencing Unit, the FIMM High Throughput Biomedicine Unit, and the FIMM Bioinformatics Unit for their excellent technical support. A&M Labor GmbH (Bergheim, Germany) is acknowledged for performing the aminopeptidase hydrolysis assay experiments. The authors are very grateful to the patients who generously donated samples for our research. The authors would also like to thank the Finnish Hematology Research Biobank (FHRB; Helsinki, Finland) for providing the viably frozen samples for the flow cytometry-based drug sensitivity testing experiments. Funding Information: Conflicts of Interest: All authors met the criteria set forth by the International Committee of Medical Journal Editors (ICMJE) and hence adequately contributed to manuscript development. A.S. and F.L. are employees of Oncopeptides AB. N.N.N. is a consultant for Oncopeptides AB. C.A.H. has received research funding from Oncopeptides AB, Kronos Bio, Novartis, Celgene, Orion Pharma, and the IMI2 consortium project HARMONY. T.G., G.A.T., and A.S. have a research contract with Oncopeptides AB. R.S. has received research funding from Amgen, BMS, Celgene, and Takeda and honoraria from Amgen, Celgene, Janssen-Cilag, Takeda, and Sanofi. J.L. and P.A. have received personal fees from Amgen, Bristol Myers Squibb, Celgene, Janssen, Sanofi, and Takeda. J.J.M., R.K., M.E.H., P.S., M.M.M., D.B., P.D., and P.O. declare no conflicts of interest. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

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