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

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.
Authors	Yiguo Hu, Yuhua Liu, Shawn Pelletier, Elisabeth Buchdunger, Markus Warmuth, Doriano Fabbro, Michael Hallek, Richard A Van Etten, Shaoguang Li
Journal	Nature genetics (Nat Genet) Vol. 36 Issue 5 Pg. 453-61 (May 2004) ISSN: 1061-4036 [Print] United States
PMID	15098032 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Benzamides CGP 76030 Enzyme Inhibitors Piperazines Proto-Oncogene Proteins Pyrimidines Pyrroles Imatinib Mesylate Protein-Tyrosine Kinases Fusion Proteins, bcr-abl HCK protein, human Hck protein, mouse Proto-Oncogene Proteins c-hck lyn protein-tyrosine kinase proto-oncogene proteins c-fgr src-Family Kinases
Topics	Animals Benzamides Burkitt Lymphoma (enzymology, pathology) Cell Division (drug effects) Drug Therapy, Combination Enzyme Activation Enzyme Inhibitors (pharmacology) Fusion Proteins, bcr-abl (metabolism) Humans Imatinib Mesylate Leukemia, Myelogenous, Chronic, BCR-ABL Positive (enzymology, pathology) Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Piperazines (pharmacology) Protein-Tyrosine Kinases (antagonists & inhibitors, physiology) Proto-Oncogene Proteins (antagonists & inhibitors, physiology) Proto-Oncogene Proteins c-hck Pyrimidines (pharmacology) Pyrroles (pharmacology) src-Family Kinases (antagonists & inhibitors, physiology)

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