Hu Yiguo, Swerdlow Sarah, Duffy Theodore M, Weinmann Roberto, Lee Francis Y, Li Shaoguang
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16870-5. doi: 10.1073/pnas.0606509103. Epub 2006 Oct 31.
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 (CML) in chronic phase but not Ph(+) B cell acute lymphoblastic leukemia (B-ALL) and CML 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 CML 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 CML 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.
人们普遍认为，伊马替尼抑制BCR-ABL的激酶活性将完全抑制其功能，导致其下游信号通路失活并治愈疾病。伊马替尼在治疗人类费城染色体阳性（Ph(+)）慢性期慢性髓性白血病（CML）方面非常有效，但对Ph(+) B细胞急性淋巴细胞白血病（B-ALL）和CML急变期无效。我们发现，在伊马替尼处理的小鼠白血病细胞中，由BCR-ABL激活的SRC激酶仍保持完全活性，这表明伊马替尼并未使所有由BCR-ABL激活的信号通路失活。这条SRC通路对于白血病细胞在伊马替尼治疗下存活以及CML转变为淋巴母细胞急变期至关重要。达沙替尼同时抑制SRC和BCR-ABL激酶活性可使B-ALL完全缓解。然而，治愈B-ALL和CML小鼠需要杀死对伊马替尼和达沙替尼均不敏感的白血病干细胞。除了BCR-ABL和SRC激酶外，干细胞通路也必须成为Ph(+)白血病治愈性治疗的靶点。
