Prolonged XPO1 inhibition is essential for optimal anti-leukemic activity in NPM1-mutated AML

NPM1 encodes for a nucleolar multifunctional protein and is the most frequently mutated gene in adult acute myeloid leukemia (AML). NPM1 mutations cause the aberrant accumulation of mutant NPM1 (NPM1c) in the cytoplasm of leukemic cells, that is mediated by the nuclear exporter Exportin-1 (XPO1). Recent work has demonstrated that the interaction between NPM1c and XPO1 promotes high homeobox (HOX) genes expression, which is critical for maintaining the leukemic state of NPM1-mutated cells. However, the XPO1 inhibitor Selinexor administered once or twice/week in early-phase clinical trials did not translate into clinical benefit for NPM1-mutated AML patients. Here, we demonstrate that this dosing strategy results in only temporary disruption of the XPO1-NPM1c interaction and transient HOX genes downregulation, limiting the efficacy of Selinexor in the context of NPM1-mutated AML. Since second-generation XPO1 inhibitors can be administered more frequently, we compared intermittent (twice/week) versus prolonged (5 days/week) XPO1 inhibition in NPM1-mutated AML models. Integrating in vitro and in vivo data, we show that only prolonged XPO1 inhibition results in stable HOX downregulation, cell differentiation and remarkable anti-leukemic activity. This study lays the groundwork for the accurate design of clinical trials with second-generation XPO1 inhibitors in NPM1-mutated AML.