PhD defence M.W.E. (Mandy) Smeets

Brief summary on the aim of the doctoral thesis:

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells can hijack the healthy bone marrow microenvironment to create a leukemic niche enabling leukemic cell survival and promoting drug resistance. Mesenchymal stromal cells (MSCs) can mimic this protective effect in co-cultures with patient-derived ALL cells. We showed that pediatric BCP-ALL cells survived better in co-culture with MSCs compared to ALL mono-culture, independently of the MSC origin (healthy, diagnosis or relapse material). Moreover, osteocytes (bone) and predominantly fibroblasts (connective tissue) provided significant survival benefit for leukemic cells. Direct cell-to-cell contact was necessary for this induced ALL survival benefit. Increased secretion of pro-inflammatory factors was observed upon contact between ALL cells and various bone marrow cells. We also found that MSCs can be used as a stable model to determine changes in MSCs induced by leukemic cells in order to unravel the mechanism by which leukemic cells gain benefit. We demonstrated that a pro-inflammatory gene signature (interferon (IFN)α/β) was upregulated in MSCs upon exposure to BCP-ALL. BCP-ALL cells and MSCs required close contact to completely activate the IFN response. Inhibition of this response did however not affect the viability and drug resistance of leukemic cells. The IFN/ response aims at activating and recruiting immune cells, not present in our MSC/BCP-ALL co-cultures. The role of migration-related factors in the leukemic niche should be addressed in future studies. Lastly, future therapies could focus on inhibiting the consequences of interactions between BCP-ALL cells and supportive cells to ensure effective targeting of the leukemic cells by (specific) drugs.