Open AccessCBL mutation-related patterns of phosphorylation and sensitivity to tyrosine kinase inhibitors
Author(s) -
Hideki Makishima,
Yuka Sugimoto,
Hadrian Szpurka,
Michael J. Clemente,
Kwok Peng Ng,
Hideki Muramatsu,
Christine L. O’Keefe,
Yogen Saunthararajah,
Jaroslaw P. Maciejewski
Publication year - 2012
Publication title -
leukemia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.539
H-Index - 192
eISSN - 1476-5551
pISSN - 0887-6924
DOI - 10.1038/leu.2012.7
Subject(s) - dasatinib , cancer research , biology , src family kinase , phosphorylation , tyrosine kinase , lapatinib , kinase , proto oncogene tyrosine protein kinase src , ectopic expression , signal transduction , microbiology and biotechnology , cell culture , genetics , trastuzumab , cancer , breast cancer
Recurrent homozygous CBL-inactivating mutations in myeloid malignancies decrease ubiquitin ligase activity that inactivates SRC family kinases (SFK) and receptor tyrosine kinases (RTK). However, the most important SFK and RTK affected by these mutations, and hence, the most important therapeutic targets, have not been clearly characterized. We compared SFK and RTK pathway activity and inhibitors in acute myeloid leukemia cell lines containing homozygous R420Q mutation (GDM-1), heterozygous deletion (MOLM13) and wild-type (WT) CBL (THP1, U937). As expected with CBL loss, GDM-1 displayed high KIT expression and granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity. Ectopic expression of WT CBL decreased GDM-1 proliferation but not cell lines with WT CBL. GDM-1, but not the other cell lines, was highly sensitive to growth inhibition by dasatinib (dual SFK and RTK inhibitor, LD50 50 nM); there was less or no selective inhibition of GDM-1 growth by sunitinib (RTK inhibitor), imatinib (ABL, KIT inhibitor), or PP2 (SFK inhibitor). Phosphoprotein analysis identified phosphorylation targets uniquely inhibited by dasatinib treatment of GDM-1, including a number of proteins in the KIT and GM-CSF receptor pathways (for example, KIT Tyr721, STAT3 Tyr705). In conclusion, the promiscuous effects of CBL loss on SFK and RTK signaling appear to be best targeted by dual SFK and RTK inhibition.