Abstract PR12: Biological insights into tumor-bone marrow microenvironment interactions derived from a humanized murine model
Authors: Sigmans Jessica , Noort Willy , Lindsley Coleman , Pan Li , Aalders Linda , Bariteau Megan , Ebert Benjamin , Aster Jon , Steidl Uli , Schuringa Jan , Yuan Huipin , Bruijn Joost de , Raymakers Reinier , Lokhorst Henk , Mutis Tuna , Martens Anton , Mitsiades Constantine , Groen Richard 
Published: May 2015

Abstract
Interactions with the hematopoietic niche in the bone marrow (BM) microenvironment are essential for hematopoietic stem cell (HSC) self-renewal. In addition, this niche is considered to serve as a sanctuary site for leukemic stem cells during chemotherapy, and contributes to disease relapse. Although many advances have been made in understanding how the niche regulates HSC self-renewal and confers therapy resistance, most of this knowledge is based on genetically engineered murine models. Given the need for models that more closely resemble the human niche, we developed a humanized model in which a scaffold seeded with human BM stromal cells generates a bone microenvironment. Inoculation of these mice with human CD34+-progenitor cells resulted in homing to the human bone environment and the generation of hematopoietic cells of distinct lineages as well as the engraftment of CD34+ cells themselves. The functionality of these humanized niches was further investigated with primary samples obtained from patients diagnosed with MDS, AML, T-ALL and MM, malignancies of which the tumor cells are highly dependent on the BM microenvironment for survival and growth. In addition, by gene-marking MM and T-ALL cells with luciferase and using bioluminescent imaging, we were able to follow tumor burden over time as well as response to therapy. Importantly, in this model, the response of primary MM cells to established anti-MM agents correlates with clinical responses of the respective patients. Moreover, this model allows us to study bidirectional interactions between MM cells and stromal cells and the resulting impact. By analyzing gene expression in human BM stromal cells (CD73+ CD90+ CD105+) that we cultured from scaffolds containing MM tumors, we identified potential novel markers for osteogenesis in MM (e.g. OGN, OMD and ASPN), as well as adhesion molecules (e.g. ITGA2) and extracellular matrix proteins (e.g. STC1 and TGM2). Hence, our model allows to investigate essential interactions within the human BM microenvironment for the development of normal and malignant hematopoiesis and thus for therapy development.
This abstract is also presented as Poster B41.
Citation Format: Jessica Sigmans, Willy Noort, Coleman Lindsley, Li Pan, Linda Aalders, Megan Bariteau, Benjamin Ebert, Jon Aster, Uli Steidl, Jan Schuringa, Huipin Yuan, Joost de Bruijn, Reinier Raymakers, Henk Lokhorst, Tuna Mutis, Anton Martens, Constantine Mitsiades, Richard Groen. Biological insights into tumor-bone marrow microenvironment interactions derived from a humanized murine model. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr PR12. doi:10.1158/1538-7445.CHTME14-PR12