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Article
Nature Genetics  36, 453 - 461 (2004)
Published online: 18 April 2004; | doi:10.1038/ng1343

Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia

Yiguo Hu1, Yuhua Liu1, Shawn Pelletier1, Elisabeth Buchdunger2, Markus Warmuth3, 5, Doriano Fabbro2, Michael Hallek3, 5, Richard A Van Etten4 & Shaoguang Li1

1  The Jackson Laboratory, 600 Main St., Bar Harbor, Maine 04609, USA.

2  Novartis Pharma AG, 4002 Basel, Switzerland.

3  Medizinische Klinik III, Universitat München, München, Germany.

4  Molecular Oncology Research Institute, Tufts-New England Medical Center, 750 Washington St., Boston, Massachusetts 02111, USA.

5  Present addresses: Genetics Institute of the Novartis Research Foundation, San Diego, California 92121, USA (M.W.); Klinik I fur Innere Medizin, Universitat zu Koln, Joseph-Stelzmann Str. 9, 50924 Koln, Germany (M.H.).

Correspondence should be addressed to Shaoguang Li sli@jax.org
The Abl kinase inhibitor imatinib mesylate is the preferred treatment for Philadelphia chromosome−positive (Ph+) chronic myeloid leukemia (CML) in chronic phase but is much less effective in CML blast crisis or Ph+ B-cell acute lymphoblastic leukemia (B-ALL). Here, we show that Bcr-Abl activated the Src kinases Lyn, Hck and Fgr in B-lymphoid cells. BCR-ABL1 retrovirus-transduced marrow from mice lacking all three Src kinases efficiently induced CML but not B-ALL in recipients. The kinase inhibitor CGP76030 impaired the proliferation of B-lymphoid cells expressing Bcr-Abl in vitro and prolonged survival of mice with B-ALL but not CML. The combination of CGP76030 and imatinib was superior to imatinib alone in this regard. The biochemical target of CGP76030 in leukemia cells was Src kinases, not Bcr-Abl. These results implicate Src family kinases as therapeutic targets in Ph+ B-ALL and suggest that simultaneous inhibition of Src and Bcr-Abl kinases may benefit individuals with Ph+ acute leukemia.

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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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