CD123 Is Consistently Expressed on NPM1-Mutated AML Cells

Simple SummaryOne-third of adult acute myeloid leukemia (AML) harbors NPM1 mutations. A deep knowledge of the distribution of selected antigens on the surface of NPM1-mutated AML cells may help optimizing new therapies for this frequent AML subtype. CD123 is known to be expressed on leukemic cells but also on healthy hematopoietic and endothelial cells, although at lower levels. Differences in antigen densities between AML and healthy cells may enlighten therapeutic windows, where targeting CD123 could be effective without triggering "on-target off-tumor" toxicities. Here, we perform a thorough analysis of CD123 expression demonstrating high expression of this antigen on both NPM1-mutated bulk leukemic cells and CD34(+)CD38(-) cells.NPM1-mutated (NPM1mut) acute myeloid leukemia (AML) comprises about 30% of newly diagnosed AML in adults. Despite notable advances in the treatment of this frequent AML subtype, about 50% of NPM1mut AML patients treated with conventional treatment die due to disease progression. CD123 has been identified as potential target for immunotherapy in AML, and several anti-CD123 therapeutic approaches have been developed for AML resistant to conventional therapies. As this antigen has been previously reported to be expressed by NPM1mut cells, we performed a deep flow cytometry analysis of CD123 expression in a large cohort of NPM1mut and wild-type samples, examining the whole blastic population, as well as CD34(+)CD38(-) leukemic cells. We demonstrate that CD123 is highly expressed on NPM1mut cells, with particularly high expression levels showed by CD34(+)CD38(-) leukemic cells. Additionally, CD123 expression was further enhanced by FLT3 mutations, which frequently co-occur with NPM1 mutations. Our results identify NPM1-mutated and particularly NPM1/FLT3 double-mutated AML as disease subsets that may benefit from anti-CD123 targeted therapies.