Prolonged XPO1 inhibition is essential to achieve optimal antileukemic activity in NPM1-mutated acute myeloid leukemia

NPM1-mutated acute myeloid leukemia (AML) accounts for one third of AML in adults. NPM1-mutated AML maintenance depends on the interaction between mutated NPM1 (NPM1c) and the nuclear exporter Exportin 1 (XPO1). In this work, we show that continous XPO1 inhibition is necessary to achieve stable disruption of the NPM1c-XPO1 interaction and to induce HOX downregulation and differentiation of AML cells with mutated NPM1. In contrast, intermittent XPO1 inhibition only results in minimal transcriptional perturbation and limited antileukemic activity. RNA-sequencing of OCI-AML3 cells treated with the XPO1 inhibitor Selinexor for either 24 or 72 hours and analyzed at 24 and 72 hours.