Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice

摘要: It is generally believed that shutting down the kinase activity of BCR-ABL by imatinib will completely inhibit its functions, leading to inactivation downstream signaling pathways and cure disease. Imatinib highly effective at treating human Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in phase but not Ph(+) B cell acute lymphoblastic (B-ALL) CML blast crisis. We find SRC kinases activated remain fully active imatinib-treated mouse leukemic cells, suggesting does inactivate all BCR-ABL-activated pathways. This pathway essential for cells survive treatment transition lymphoid Inhibition both activities dasatinib affords complete B-ALL remission. However, curing mice requires killing stem insensitive dasatinib. Besides kinases, must be targeted curative therapy leukemia.