Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia
Top Cited Papers
- 18 April 2004
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 36 (5), 453-461
- https://doi.org/10.1038/ng1343
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.Keywords
This publication has 37 references indexed in Scilit:
- Molecular mechanisms of transformation by the BCR-ABL oncogeneSeminars in Hematology, 2003
- The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cellsThe EMBO Journal, 2002
- Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemiaCancer Cell, 2002
- Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loopProceedings of the National Academy of Sciences of the United States of America, 2002
- High frequency of point mutations clustered within the adenosine triphosphate–binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistanceBlood, 2002
- Hematologic and Cytogenetic Responses to Imatinib Mesylate in Chronic Myelogenous LeukemiaNew England Journal of Medicine, 2002
- Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or AmplificationScience, 2001
- Activity of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in the Blast Crisis of Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia with the Philadelphia ChromosomeNew England Journal of Medicine, 2001
- Chronic Myeloid LeukemiaNew England Journal of Medicine, 1999
- The Src Family Kinase Hck Interacts with Bcr-Abl by a Kinase-independent Mechanism and Phosphorylates the Grb2-binding Site of BcrPublished by Elsevier BV ,1997