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Utilizing BMP-2 muteins for treatment of multiple myeloma

Please always quote using this URN: urn:nbn:de:bvb:20-opus-158144
  • Multiple myeloma (MM) represents a haematological cancer characterized by the pathological hyper proliferation of antibody-producing B-lymphocytes. Patients typically suffer from kidney malfunction and skeletal disorders. In the context of MM, the transforming growth factor β (TGFβ) member Activin A was recently identified as a promoter of both accompanying symptoms. Because studies have shown that bone morphogenetic protein (BMP)-2-mediated activities are counteracted by Activin A, we analysed whether BMP2, which also binds to the Activin AMultiple myeloma (MM) represents a haematological cancer characterized by the pathological hyper proliferation of antibody-producing B-lymphocytes. Patients typically suffer from kidney malfunction and skeletal disorders. In the context of MM, the transforming growth factor β (TGFβ) member Activin A was recently identified as a promoter of both accompanying symptoms. Because studies have shown that bone morphogenetic protein (BMP)-2-mediated activities are counteracted by Activin A, we analysed whether BMP2, which also binds to the Activin A receptors ActRII and ActRIIB but activates the alternative SMAD-1/5/8 pathway, can be used to antagonize Activin A activities, such as in the context of MM. Therefore three BMP2 derivatives were generated with modified binding activities for the type II (ActRIIB) and/or type I receptor (BMPRIA) showing either increased or decreased BMP2 activity. In the context of MM these BMP2 muteins show two functionalities since they act as a) an anti-proliferative/apoptotic agent against neoplastic B-cells, b) as a bone-formation promoting growth factor. The molecular basis of both activities was shown in two different cellular models to clearly rely on the properties of the investigated BMP2 muteins to compete for the binding of Activin A to the Activin type II receptors. The experimental outcome suggests new therapeutic strategies using BMP2 variants in the treatment of MM-related pathologies.show moreshow less

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Metadaten
Author: Axel Seher, Charlotte Lagler, Thorsten Stühmer, Urs Dietmar Achim Müller-Richter, Alexander Christian Kübler, Walter Sebald, Thomas Dieter Müller, Joachim Nickel
URN:urn:nbn:de:bvb:20-opus-158144
Document Type:Journal article
Faculties:Medizinische Fakultät / Theodor-Boveri-Institut für Biowissenschaften
Medizinische Fakultät / Klinik und Poliklinik für Mund-, Kiefer- und Plastische Gesichtschirurgie
Medizinische Fakultät / Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II)
Medizinische Fakultät / Lehrstuhl für Tissue Engineering und Regenerative Medizin
Language:English
Parent Title (English):PLoS ONE
Year of Completion:2017
Volume:12
Issue:5
Pagenumber:e0174884
Source:PLoS ONE 12(5): e0174884 (2017). DOI: 10.1371/journal.pone.0174884
DOI:https://doi.org/10.1371/journal.pone.0174884
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:B cell receptors; B cells; BMP; cell binding; cell proliferation; gene expression; membrane receptor signaling; multiple myeloma; signaling
Release Date:2018/03/21
Collections:Open-Access-Publikationsfonds / Förderzeitraum 2017
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International