Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice.
Document Type
Article
Publication Date
2006
Keywords
Antineoplastic-Agents, B-Lymphocytes, Blast-Crisis, Cell-Line-Tumor, Cell-Transformation-Neoplastic, Fusion-Proteins-bcr-abl, Humans, Leukemia-B-Cell-Acute, Leukemia-Myeloid-Philadelphia-Positive, Mice-Inbred-BALB-C, Mice-Inbred-C57BL, Mice-Knockout, Piperazines, Protein-Kinase-Inhibitors, Pyrimidines, Thiazoles, Tumor-Stem-Cells, src-Family-Kinases
First Page
16870
Last Page
16875
JAX Source
Proc Natl Acad Sci U S A 2006 Nov; 103(45):16870-5.
Abstract
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.
Recommended Citation
Hu Y,
Swerdlow S,
Duffy TM,
Weinmann R,
Lee FY,
Li S.
Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc Natl Acad Sci U S A 2006 Nov; 103(45):16870-5.