期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 45, 页码 16870-16875出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0606509103
关键词
dasatinib; imatinib; SRC kinases
资金
- NCI NIH HHS [R01 CA114199, CA 114199] Funding Source: Medline
It is generally believed that shutting down the kinase activity of BCR-ABL by imatinib will completely inhibit its functions, leading to inactivation of its downstream signaling pathways and cure of the disease. Imatinib is highly effective at treating human Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CIVIL) in chronic phase but not Ph+ B cell acute lymphoblastic leukemia (B-ALL) and CIVIL blast crisis. We find that SRC kinases activated by BCR-ABL remain fully active in imatinib-treated mouse leukemic cells, suggesting that imatinib does not inactivate all BCR-ABL-activated signaling pathways. This SRC pathway is essential for leukemic cells to survive imatinib treatment and for CIVIL transition to lymphoid blast crisis. Inhibition of both SRC and BCR-ABL kinase activities by dasatinib affords complete B-ALL remission. However, curing B-ALL and CIVIL mice requires killing leukemic stem cells insensitive to both imatinib and dasatinib. Besides BCR-ABL and SRC kinases, stem cell pathways must be targeted for curative therapy of Ph+ leukemia.
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