Inhibition of RAN/XPO1 impairs survival of CML but not normal CD34⁺ cord blood cells. (A) CD34⁺ cells from normal cord blood (n = 2) were either infected with doxycycline-inducible shRAN and plated in semisolid medium with and without 2.5 µM imatinib (i) or plated in semisolid medium in the presence or absence of graded concentrations of KPT-330 (ii-iii). Colonies were counted after 14 days. RAN inhibition had no effect on survival of normal CD34⁺ cord blood cells. (B) CD34⁺ cells from newly diagnosed CML patients were either infected with shRAN (i) or treated with KPT-330 (ii) and analyzed for colony formation in the indicated conditions. Inhibition of XPO1 by treatment with KPT-330 also resulted in enhanced levels of nuclear RAN, SET, and p53 in CD34⁺ cells from newly diagnosed CML patients. Lamin B was analyzed to control for nuclear fractionation and α-tubulin for cytoplasmic fractionation. (C) CD34⁺ cells from patients with clinical TKI resistance were either infected with shRAN or treated with KPT-330 and analyzed for colony-forming ability. shRAN and KPT-330 significantly reduced survival of CML CD34⁺ cells from TKI-resistant patients with wild-type BCR-ABL1 (i), but not from a patient with BCR-ABL1^T315I (ii). Error bars represent SEM; *P < .05. Because only 1 BCR-ABL1^T315I patient sample was analyzed, standard errors are not provided.