Op 14 december 2012 behaalde Dehui Xu aan de faculteit geneeskunde en farmacie van de VUB de titel van doctor in de medische wetenschappen (PhD in medical sciences) voor zijn onderzoek met als titel: “The Role of Dll1/Notch Pathway in Multiple Myeloma Cell Proliferation, Engraftment and Drug Resistance” Dit onderzoek werd uitgevoerd binnen de onderzoeksgroep hematologie-immunologie, onder leiding van Prof. dr. Karin Vanderkerken en Prof. Dr. Els Van Valckenborgh. Met dit werk werd aangetoond dat de interactie van Dll1, uitgedrukt op beenmerg stromale cellen, en Notch receptor, uitgedrukt op myeloom cellen, zorgt voor een activatie van Notch signaalweg in myeloom cellen. Deze activatie zal leiden tot een clonogene tumorgroei en een versnelling van myeloom ontwikkeling. Ook werd aangetoond dat Notch activatie in myeloom cellen zorgt voor een mindere gevoeligheid aan de proteasoom inhibitor bortezomib (Velcade). De Notch activatie kan worden geblokkeerd met een bepaald produkt genaamd DAPT. Met muizen werd aangetoond dat een behandeling van bortezomib samen met DAPT zorgt voor een betere overleving van de zieke muizen. Deze studie geeft dus aan dat blokkering van de Notch signaalweg een potentiële strategie kan zijn om resistentie tegen bortezomib en myeloomgroei tegen te gaan.
English summary of the thesis
Relapse and drug resistance are two main challenges in MM treatments. The BM microenvironment plays a critical role in MM pathogenesis and development. Notch receptors and ligands are expressed both in MM cells and the BM microenvironment. In this study, we demonstrated that Dll1 is present on BM stromal cells and Notch1 and Notch2 receptors were expressed by MM cells. Baskiri Moreover, Dll1/Notch interaction could activate Notch signaling in MM cells mostly by Notch2 activation.We found that Dll1/Notch interaction could promote MM clonogenic growth and accelerate MM development in vivo. Furthermore, we demonstrated that Dll1/Notch activation accelerates MM development mainly by promoting MM cell proliferation predominantly in CD138+ MM cells, by reducing the expression of p21 and p27 thus accelerating MM cell cycling. Next, we described that Dll1/Notch activation could induce drug resistance to bortezomib and DAPT could reverse the effect. CYP1A1, which is involved in drug metabolism, was upregulated by Dll1/Notch interaction. We further confirmed that inhibiting CYP1A1 by either α-Naphthoflavone (inhibitor) or CYP1A1-siRNA increases the sensitivity to bortezomib, suggesting that CYP1A1 is involved in bortezomib resistance. In addition, in vivo data showed that combination treatment of DAPT with bortezomib was able to increase bortezomib sensitivity and prolonged overall survival in the 5T33MM mouse model. Our study provides a potential strategy not only to overcome bortezomib resistance but also to delay or avoid relapse by Notch inhibition in MM therapy.
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