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

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