Mechanisms of oncogene kinase-independent resistance to TKI therapy in CML with wild-type BCR-ABL1 and FLT3-ITD⁺ AML. The expression of the nuclear export factors RAN and XPO1 was found to be increased in CML and AML in an oncogene kinase-independent manner and likely through either signals generated by the microenvironment or by cell-autonomous BCR-ABL or FLT3-ITD kinase-independent signals (A). This results in increased nuclear export of their cargo that also is comprehensive of oncogenic signal transducers (eg, SET) and tumor-suppressor proteins (eg, p53) that if delocalized become activated and inactivated, respectively. Such an effect together with the BCR-ABL1- or FLT3-ITD-generated oncogenic signals will both enhance proliferation and/or survival of myeloid progenitors. Interestingly, Khorashad et al¹  show that the activity of XOP1 and RAN seems to specifically control those oncogene kinase-independent molecular events leading to resistance to TKI-induces apoptosis. Khorashad et al¹  reported that inhibition of nuclear export by downregulation of RAN or pharmacologic inhibition of XPO1 activity by the clinically relevant karyopherin inhibitor KPT-330 results in nuclear accumulation of their cargo and, consequently, restored sensitivity of leukemic progenitors to TKI-induced inhibition of proliferation and/or survival and restoration of sensitivity to TKI treatment (B).