Leukemia is one of the most common types of cancer. Even though there are ways to treat leukemia with an allogeneic stem cell transplantation, people can suffer from a relapse and the disease can often be lethal. The goal of this project is to study the role of the leukemic microenvironment in the bone marrow, more specifically in the hematopoietic stem cell niche, where the hematopoietic stem cells (HSCs) and the mesenchymal stem/stromal cells (MSCs) are located. Both cell types play an essential role in the stem cell niche and accordingly influence the development of leukemia. In this study, we aim to identify whether the first steps in leukemia development is the malignant transformation of hematopoietic cells or whether the formation of a malignant microenvironment is the initial step. For this purpose, the interactions of leukemic and healthy hematopoietic and stromal cells with their environment and their interplay will be investigated. To mimic the bone marrow in health and leukemia, we will take advantage of a macroporous cationized bovine serum albumin (cBSA) hydrogel developed earlier by the group as a 3D in vitro model of the HSC niche.

These hydrogels will be seeded with HSCs and MSCs from healthy donors to mimic the healthy stem cell niche. A 3D co- culture of MSCs from a leukaemia patient and HSCs from a healthy donor resembles the situation after stem cell transplantation. A culture of healthy MSCs and leukemic blasts from leukemia patients allows us to analyze the effect of leukemic cells on the bone marrow shortly after the outbreak of the disease, the combination of MSCs and blasts from leukemia patients will enable the mimicry of leukemic bone marrow later during later stages of the disease.

First results from such cross experiments with leukemic cell lines showed a clear effect. There is an impact of the leukemic cell lines on the healthy MSC as well as an effect of the leukemic MSC on the HSC. This is particularly apparent in the alteration of surface markers and cytokine profiles. The results provide evidence that the HSC niche is altered in leukemia patients in a way that may might impede successful therapy. In a next step, these results are transferred to primary cells from leukemic donors to more closely mimic the in vivo conditions of a malignant stem cell niche in vitro. Analyzing these models will not only allow to address the question who comes first – the malignant niche or the malignant cell, but also to create patient-specific models that could be used as a drug-testing platform for pharmaceuticals.