Page 11 - Haematologica - Vol. 105 n. 6 - June 2020

Editorials
of more primitive leukemic cell populations will hold the key to durable disease control. It seems possible that most cancer therapeutics utilized to date are simply more active against more mature cell types based on targeting of bio- logical programs that are more prominent in these more mature cells. The identification of drugs that show inversely preferential activity against the more primitive cell states is an example of the enormous benefit that can be derived from this updated platform for flow cytometric drug sensitivity assessment.
Majumder et al. speculate that their profiling will open
new opportunities for other disease indications. As exam- ples, they note that dexamethasone and midostaurin tar- geted NK cells as effectively as B cells, suggesting their potential clinical use in NK-cell malignancies. They further envision incorporating cell lineage specific drug responses into the regimen for preclinical drug development will identify unexpected therapeutic niches for small mole- cules and enhanced therapeutic precision. Their study pro- vides additional support for the concept of using multiple diagnostic technologies to enhance precision therapy. Indeed, the use of this technology platform to identify
Figure 1. High-throughput flow cytometry functional screening strategy identifies drug effects on discrete cell lineages. (A) Schematic for screening workflow where- by cells from leukemia patient samples are exposed to a library of drugs and then subjected to flow cytometry using antibodies to distinguish discrete cell populations, such as T cells (CD3), B cells (CD19), monocytes (CD14), hematopoietic stem/progenitor cells (CD34), etc. (B) Results from the workflow in (A) have shown that drugs have differential effects on cell lineage states, which are often conserved between malignant and healthy settings. As an example, the BCL2 inhibitor, venetoclax, was shown to have more effect against less differentiated cells as well as mature B cells and less impact on mature monocytes and granulocytes in cells from healthy donors. This observation extended to these same cell states in leukemia patient samples, where venetoclax was more effective in killing mature B cells in chronic lymphocytic leukemia and leukemic progenitor cells in acute myeloid leukemia (AML), but was less effective against malignant monocytes in the same AML samples.
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