Targeting acute myeloid leukaemia via the leukaemic matrisome interface

Acute myeloid leukaemia is the most common and deadliest form of blood cancers. While previously the focus of research has been on genetic changes, I focused on the extracellular matrix (ECM), which surrounds and connects the cells within the tissue.

I developed and used an in vitro bone marrow system to study the interactions of leukaemia cells and bone cells via the ECM. These interactions are suspected to lead to resistance to chemotherapy and subsequently relapse of AML patients. For our model bone cells (osteoblasts, OB) were cultivated together with acute myeloid leukaemia (AML) cells for up to three weeks. I monitored the cultures for changes in behaviour, gene expression and extracellular protein secretion. In essence, when cultured together with AML cells, OB showed a reduced ability to differentiate into mature osteocytes. This was marked by the reduction of OB marker genes as well as changes in the extracellular matrix and matrix mineralisation. AML cells on the other hand, show and increased proportion of stem cells, which leads to increased resistance to chemotherapeutic drugs. Analysis on single cell level revealed, that AML cells not only influence gene expression and matrix production of OB cells, but also produce a waste majority of ECM proteins themselves. Furthermore, I could show that the altered ECM alone is capable of transferring the leukemic properties onto new OB and AML cells. Interestingly, ECM that was derived from drug treated co-cultures seems to increase the survival of freshly added AML cells when treated with the chemotherapeutic drug.

Taken together, these findings indicate that the ECM plays a bigger role in the formation of the leukemic bone marrow niche as well as the protection of AML cells from treatment than previously anticipated. The changes in the ECM that I discovered, could be a promising target to improve treatment and survival of AML patients.