Hsp90 is a therapeutic target for CML induced by either BCR-ABL-WT or BCR-ABL-T315I. (A) Treatment with the Hsp90 inhibitor IPI-504 prolonged survival of CML mice. Mice with BCR-ABL-WT (left panel)– or BCR-ABL-T315I (right panel)–induced CML were treated with placebo (n = 15 for BCR-ABL-WT; n = 13 for BCR-ABL-T315I), imatinib (100 mg/kg, twice a day by gavage) (n = 8 for both BCR-ABL-WT and -T315I), IPI-504 (50 mg/kg, once every 2 days by gavage) (n = 20 for both BCR-ABL-WT and BCR-ABL-T315I), IPI-504 (100 mg/kg, once every 2 days by gavage) (n = 8 for both BCR-ABL-WT; n = 7 for BCR-ABL-T315I), and imatinib + IPI-504 (n = 12 for both BCR-ABL-WT and -T315I), respectively, beginning at day 8 after transplantation. The IPI-504–treated mice with BCR-ABL-T315I–induced CML lived longer than those with BCR-ABL-WT–induced CML (comparing between left and right panels). (B) Flow cytometric evaluation of the leukemic process in IPI-504– or imatinib-treated CML mice. The number of circulating leukemic cells (calculated as percentage of Gr-1⁺ GFP⁺ cells × white blood cell count) in mice with BCR-ABL-WT (left panel)– or BCR-ABL-T315I (right panel)–induced CML treated with placebo, imatinib, IPI-504, or the combination of imatinib and IPI-504 was determined on day 14 after transplantation. (C) Spleen weights of CML mice treated with placebo, imatinib, IPI-504, and combination of imatinib and IPI-504. (Left panel) BCR-ABL-WT. (Right panel) BCR-ABL-T315I. (D) Photomicrographs of hematoxylin and eosin–stained lung sections from drug-treated mice at day 14 after transplantation. (E) Western blot analysis of spleen-cell lysates for degradation of BCR-ABL in IPI-504–treated CML mice. IB indicates immunoblot.