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

Nature Genetics volume 36, pages 453–461 (2004)Cite this article

Abstract

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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Figure 1: Activation of Src kinases by Bcr-Abl.
Figure 2: Src kinases are required for induction of B-ALL but not CML by Bcr-Abl.
Figure 3: The Src kinase inhibitor CGP76030 inhibits activation of Lyn, Hck and Fgr in pre-B cells expressing Bcr-Abl.
Figure 4: CGP76030 inhibits proliferation and induces apoptosis of pre-B cells expressing Bcr-Abl.
Figure 5: Src kinases are therapeutic targets in Bcr-Abl-induced B-ALL but not in CML.
Figure 6: Flow cytometric and histopathological evaluation of the leukemic process in mice treated with kinase inhibitor.
Figure 7: CGP76030 inhibits proliferation and induces apoptosis of pre-B cells expressing the Bcr-Abl T315I mutant that is resistant to inhibition by imatinib and CGP76030.

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Acknowledgements

We thank C. Lowell for Lyn−/− Hck−/− Fgr−/− mice; A. Wood and P. Lassota for discussions; K. Paigen, B. Tennent and S. Sampson for critically reading the manuscript; and P. Cherry for the secretarial assistance. This work was supported by the institutional funds from The Jackson Laboratory and grants from the Irving A. Hansen Foundation and The V Foundation for Cancer Research to S.L., who is a Scholar of The V Foundation for Cancer Research, and by a grant from the US National Institutes of Health and a Leukemia and Lymphoma Society SCOR grant to R.A.V., who is a Stohlman Scholar of the Leukemia and Lymphoma Society.

Author information

Author notes

  1. Markus Warmuth

    Present address: Genetics Institute of the Novartis Research Foundation, San Diego, California, 92121, USA

  2. Michael Hallek

    Present address: Klinik I fur Innere Medizin, Universitat zu Koln, Joseph-Stelzmann Str. 9, 50924, Koln, Germany

Authors and Affiliations

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

    Yiguo Hu, Yuhua Liu, Shawn Pelletier & Shaoguang Li

  2. Novartis Pharma AG, Basel, 4002, Switzerland

    Elisabeth Buchdunger & Doriano Fabbro

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

    Markus Warmuth & Michael Hallek

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

    Richard A Van Etten

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Hu, Y., Liu, Y., Pelletier, S. et al. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet 36, 453–461 (2004). https://doi.org/10.1038/ng1343

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