Leukemia-targeting ligands isolated from phage-display peptide libraries.
Ligands specifically binding to leukemia cells may be used for drug targeting, resulting in more effective treatment with less side effects. Little is known about receptors specifically expressed on acute myeloid leukemia (AML) cells or ligands thereof. We selected random phage display peptide libraries on Kasumi-1 AML cells. A peptide with the sequence CPLDIDFYC was enriched. Phage displaying this peptide strongly bound to Kasumi-1 and SKNO-1 cells and binding could be inhibited by the cognate peptide. Both, Kasumi-1 and SKNO-1 cells carry the chromosomal translocation t(8;21), leading to aberrant expression of the fusion protein AML1/ETO. CPLDIDFYC also strongly and specifically bound primary AML1/ETO-positive AML blasts as well as U-937 cells with forced AML1/ETO expression, suggesting that the CPLDIDFYC receptor may be upregulated upon AML1/ETO expression. Gene expression profiling comparing a panel of CPLDIDFYC-binding and CPLDIDFYC-nonbinding cell lines identified a set of potential receptors for the CPLDIDFYC peptide. Further analysis suggested that alpha4beta1 integrin (VLA-4) is the CPLDIDFYC receptor. Finally, we showed that the CPLDIDFYC-phage is internalized upon receptor binding, suggesting that the CPLDIDFYC-receptor-ligand interaction may be exploitable for targeting drugs or gene therapy vectors to leukemia cells carrying the suitable receptor.
Jäger
S
S
Department of Hematology and Oncology, University of Freiburg Medical Center, Freiburg, Germany.
Jahnke
A
A
Wilmes
T
T
Adebahr
S
S
Vögtle
F-N
FN
Delima-Hahn
E
E
Pfeifer
D
D
Berg
T
T
Lübbert
M
M
Trepel
M
M
D000208:Acute Disease; D000368:Aged; D045744:Cell Line, Tumor / Q000378:metabolism; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics / Q000648:ultrastructure; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics / Q000648:ultrastructure; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000502:physiology; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D004705:Endocytosis; D005260:Female; D020869:Gene Expression Profiling; D015316:Genetic Therapy; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000235:genetics / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology; D008024:Ligands; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000378:metabolism; D009842:Oligopeptides / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology; D019151:Peptide Library; D011485:Protein Binding; D000075142:RUNX1 Translocation Partner 1 Protein; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000378:metabolism; D014178:Translocation, Genetic
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D039041:Integrin alpha4beta1; D008024:Ligands; D009363:Neoplasm Proteins; D009842:Oligopeptides; D015514:Oncogene Proteins, Fusion; D019151:Peptide Library; D000075142:RUNX1 Translocation Partner 1 Protein; D011955:Receptors, Drug