Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia.
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.
Hu
Yiguo
Y
The Jackson Laboratory, 600 Main St., Bar Harbor, Maine 04609, USA.
Liu
Yuhua
Y
Pelletier
Shawn
S
Buchdunger
Elisabeth
E
Warmuth
Markus
M
Fabbro
Doriano
D
Hallek
Michael
M
Van Etten
Richard A
RA
Li
Shaoguang
S
D000818:Animals; D001549:Benzamides; D002051:Burkitt Lymphoma / Q000201:enzymology* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004359:Drug Therapy, Combination; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010879:Piperazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051572:Proto-Oncogene Proteins c-hck; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D001549:Benzamides; C472714:CGP 76030; D004791:Enzyme Inhibitors; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D011758:Pyrroles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C496631:HCK protein, human; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; C060902:lyn protein-tyrosine kinase; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases