Determining the supporting mesenchymal cell lineages and their interactions with multiple myeloma
Final Report Abstract
In summary, the panEbfRNAi mouse line initially was planned to be the main tool to analyse which mesenchymal cell populations contribute to the support of multiple myeloma cells. To our surprise the RNAi construct did not lead to a down-regulation of Ebf family members in vivo as was the case in cell culture experiments. However, we discovered that Ebf2-expressing cells are able to support malignant hematopoietic cells, and that the loss of Ebf2 impairs this ability. Therefore, we continued in analysing the transcriptional profile of purified Ebf2-positive cells, with the aim of identifying secreted and transmembrane proteins that are implicated in the support of normal and malignant hematopoietic cells. We discovered inhibitors of the wnt signalling pathway as deregulated in absence of Ebf2 and concentrated on the analysis of members of the Sfrp and Dkk family. In case of Sfrp2 we discovered a role in the support of normal immature hematopoietic cells, and are currently investigating an involvement in the support of malignant hematopoietic cells. Dkk-1 levels prove to be a prognostic marker in prostate cancer. Furthermore, we were able to establish a novel role for the secreted protein Dpt in the support of immature hematopoietic cells, a link that we are also following with respect to the support of malignant hematopoietic cells.
Publications
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Maintenance of hematopoiesis: Role of early B cell factor 2. In: Stem Cells and Cancer Stem Cells. Springer 2012; ISSN/ISBN 978-94-007-2827-1
Kieslinger M
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A miRNA-based approach to down-regulate a gene family in vivo. PLOS One. 2013;8:80312
Kim J, Badaloni A, Willert T, Zimber-Strobl U, Kühn R, Wurst W, Kieslinger M
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Ebf factors and MyoD cooperate to regulate muscle relaxation via Atp2a1. Nat Commun. 2014;5:3793
Jin S, Kim J, Willert T, Klein-Rodewald T, Garcia-Dominguez M, Mosqueira M, Fink R, Esposito I, Hofbauer LC, Charnay P, Kieslinger M
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High serum levels of Dickkopf-1 are associated with a poor prognosis in prostate cancer patients. BMC Cancer. 2014,14:649
Rachner TD, Thiele S, Göbel A, Browne A, Fuessel S, Erdmann K, Wirth MP, Fröhner M, Todenhöfer T, Muders MH, Kieslinger M, Rauner M, Hofbauer LC
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Identification of factors promoting ex vivo maintenance of mouse hematopoietic stem cells by long-term single-cell quantification. Blood. 2016;128:1181-92
Kokkaliaris KD, Drew E, Endele M, Loeffler D, Hoppe PS, Hilsenbeck O, Schauberger B, Hinzen C, Skylaki S, Theodorou M, Kieslinger M, Lemischka I, Moore K, Schroeder T
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Loss of Sfrp2 in the niche amplifies stress-induced cellular responses, and impairs the in vivo regeneration of the hematopoietic stem cell pool. Stem Cells. 2016;34:2381-92
Ruf F, Schreck C, Wagner A, Grziwok S, Pagel C, Romero S, Kieslinger M, Shimono A, Peschel C, Götze KS, Istvanffy R, Oostendorp RA
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Spatiotemporal patterning of EpCAM is important for murine embryonic endo- and mesodermal differentiation. Sci Rep. 2018;8:1801
Sarrach S, Huang Y, Niedermeyer S, Hachmeister M, Fischer L, Gille S, Pan M, Mack B, Kranz G, Libl D, Merl-Pham J, Hauck SM, Paoluzzi Tomada E, Kieslinger M, Jeremias I, Scialdone A, Gires O
