In vitro simulation of the acute lymphoblastic leukemia niche: a critical view on the optimal approximation for drug testing.

Acute lymphoblastic leukemia (ALL) with the worst prognosis is related to minimal residual disease, MRD. MRD not only depends on the individual peculiarities of leukemic clones but also reflects the protective role of the ALL microenvironment. In this review we discuss in detail cell-to-cell interactions in the two leukemic niches, more explored bone marrow (BM) and less studied extramedullary adipose tissue (EMAT). A special emphasis is given to multiple ways of interactions of ALL cells with BM or EMAT microenvironment, indicating observed differences in B- and T-ALL behavior. This analysis argued for the usage of co-culture systems for drug testing. Starting with a review of available sources and characteristics of ALL cells, mesenchymal stromal cells (MSC), endothelial cells and adipocytes, we have then made an update of the available 2D and 3D systems, which bring together cellular elements, components of the extracellular matrix (ECM) or its imitation. We discussed the most complex available 3D systems like "leukemia-on-a-chip", which include either a prefabricated microfluidics platform or, alternatively, the microarchitecture, designed by using the 3D bioprinting technologies. From our analysis it follows that for preclinical antileukemic drug testing in most cases intermediately complex in vitro cell systems are optimal, such as a "2.5D" co-culture of ALL cells with niche cells (MSC, endothelial cells) plus matrix components or scaffold-free MSC organoids, populated by ALL cells. Due to emerging evidence for the correlation of obesity and poor prognosis, a co-culture of adipocytes with ALL cells as a drug testing system is gaining shape.