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Dll1/Notch activation accelerates multiple myeloma disease development by promoting CD138+ MM-cell proliferation

Leukemia volume 26, pages 1402–1405 (2012)Cite this article

Multiple myeloma (MM) is a B-cell malignancy characterized by the accumulation of aberrant plasma cells in the patients’ bone marrow (BM). Relapse often occurs after recovery of MM patients from chemotherapy and has become one of the greatest challenges in MM treatment. The BM microenvironment has a critical role in MM-cell growth and survival. Several pathways, such as MAPK, p53, JAK/STAT3, RANK/RANKL/OPG, NF-κB and WNT are involved in the process of MM development. The Notch signaling is a highly conserved pathway that regulates cell-fate determination, stem cell self-renewal, proliferation and apoptosis.1 In this pathway, four receptors (Notch1-4) and several ligands (Jag1-2, Dll1, Dll3-4) have been described. These receptors and ligands were detected both in MM cells and in BM stromal cells.2, 3, 4, 5 Furthermore, it has been described in human MM that Jag1- and Jag2-induced Notch activation resulted in MM-cell proliferation and that Notch1 signaling is involved in drug resistance.2, 3, 4 Controversially, Zweidler-McKay et al.6 claimed that constitutive activation of Notch by Notch intracellular domain (NICD1-4) transduction inhibited malignant B-cell growth and induced apoptosis. The role of the Dll1/Notch pathway in myeloma cell proliferation and clonogenic growth as well as disease engraftment has not yet been studied. We investigated this pathway using the 5T33MM murine model that mimics the human MM disease closely as described previously.7 The human MM cell lines MMS-1 and LP-1 were used to confirm our obtained mouse data.

Subsequently, we investigated the role of Dll1/Notch interaction in MM disease development and in vivo engraftment in the 5T33MM murine model. 5T33MMvt cells cocultured with MS5 or MS5.Dll1 stromal cells for 6 days were harvested, counted and viability was tested with the Cell Titer-Glo assay (Promega, Leiden, The Netherlands). MM cells (200 μl) were injected intravenously into naive C57Bl/KaLwRij mice at 0.5 million cells/mouse. Mice injected with Dll1-activated 5T33MMvt cells developed disease faster than those injected with the control cells (Figure 3c), and also had a higher serum M spike concentration (1.98±0.44 g/dl, n=3) compared with control mice (0.95±0.02 g/dl, n=3), suggesting that Notch activation not only promoted MM clonogenic growth in vitro but also accelerated MM development in vivo. Furthermore, 5T33MMvt cells pretreated with 10 μM DAPT (Dimethyl sulfoxide (DMSO) as control) for 6 days, to inhibit constitutive Notch pathway activation, were injected into naive mice. DMSO- and DAPT-treated cells had the same viability when injected, as analyzed by the Cell Titer-Glo assay. After an average of 59 days, the DMSO control group became sick with an average M-compound of 1.78±0.14 g/dl (n=6), whereas in the DAPT group, all mice looked healthy and no serum M compound could be detected at that time. The DAPT-treated group did develop MM disease, at a significantly later time point (average of 161 days after injection) with a lower M-compound concentration (0.35±0.13 g/dl, n=6), suggesting that the Notch pathway has a critical role in MM initiation and development (Figure 3d).

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Acknowledgements

We would like to thank Dr Françoise Pflumio from the Université Paris Descartes, France, for her kindness of donating the MS5 and MS5.Dll1 stromal cell lines for our research. We also thank Angelo Willems and Carine Seynaeve for their expert technical assistance. Our research work is supported by grants from CSC-VUB Scholarship, European Union (MSCNET, LSHC-CT-2006-037602) and Over-Myr (EU-FP7), Vlaamse Kankerliga and Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (FWO). Eline Menu, Elke De Bruyne and Els Van Valckenborgh are post-doctoral fellows of FWO.

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  1. K Vanderkerken and E Van Valckenborgh: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium

    D Xu, J Hu, S Xu, E De Bruyne, E Menu, B Van Camp, K Vanderkerken & E Van Valckenborgh

  2. Department of Molecular Biology and Genetics, Medical School of Xi’an Jiaotong University, Xi’an, China

    D Xu & J Hu

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Xu, D., Hu, J., Xu, S. et al. Dll1/Notch activation accelerates multiple myeloma disease development by promoting CD138+ MM-cell proliferation. Leukemia 26, 1402–1405 (2012). https://doi.org/10.1038/leu.2011.332

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