Model of XPO1, STAT3, and selinexor interactions in normal and impaired thrombopoiesis based on the findings of Machlus et al. Binding of TPO by c-Mpl on MK progenitors (A) triggers multiple events, including activation of the JAK2/STAT3 pathway. The accumulation of pSTAT3 in the nucleus is normally limited by XPO1-mediated export of STAT3 to the cytoplasm, but XPO1 inhibition by selinexor (B) allows accumulation of nuclear STAT3, which can be phosphorylated (P) to its active form. These events lead to upregulation of Klf4 and downstream genes, including Oct4, which promotes an undifferentiated state countering the prodifferentiation TPO signal. Thus, selinexor treatment impairs TPO-dependent MK maturation and promotes the onset of thrombocytopenia. See Figure 6G in the article by Machlus et al that begins on page 1132.