Identification of new possible targets for leukemia treatment by kinase activity profiling.
To date, the biology of acute leukemia has been unclear, and defining new therapeutic targets without prior knowledge remains complicated. The use of high-throughput techniques would enable us to learn more about the biology of the disease, and make it possible to directly assess a broader range of therapeutic targets. In this study we have identified comprehensive tyrosine kinase activity profiles in leukemia samples using the PamChip® kinase activity profiling system. Strikingly, 31% (44/120) of the detected peptides were active in all three groups of leukemia samples. The recently reported activity of platelet-derived growth factor receptor (PDGFR) and neurotrophic tyrosine kinase receptors (NTRK1 and NTRK2) in leukemia could be appreciated in our array results. In addition, high levels of peptide phosphorylation were demonstrated for peptides related to macrophage stimulating 1 receptor (MST1R). A provisional signal transduction scheme of the common active peptides was constructed and used to specifically select an inhibitor for leukemic blast cell survival assays. As expected, a dose-dependent decrease in leukemic blast cell survival was achieved for all leukemia samples. Our data demonstrate that kinase activity profiling in leukemic samples is feasible and provides novel insights into the pathogenesis of leukemia. This approach can be used for the rapid discovery of potential drug targets.
Department of Pediatric Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Arja
A
Ter Elst
Sander H
SH
Diks
Kim R
KR
Kampen
Peter M
PM
Hoogerbrugge
Rob
R
Ruijtenbeek
Piet J
PJ
Boender
Arend H
AH
Sikkema
Frank J G
FJ
Scherpen
Willem A
WA
Kamps
Maikel P
MP
Peppelenbosch
Eveline S J M
ES
de Bont
D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D007938:Leukemia / Q000201:enzymology* / Q000473:pathology; D010446:Peptide Fragments / Q000032:analysis*; D010766:Phosphorylation; D040081:Protein Array Analysis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism
D010446:Peptide Fragments; D011505:Protein-Tyrosine Kinases; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020813:Receptor, trkB; D017479:Receptors, Platelet-Derived Growth Factor