Leukemia-targeting ligands isolated from phage-display peptide libraries

TY - JOUR

T1 - Leukemia-targeting ligands isolated from phage-display peptide libraries

AU - Jäger, S

AU - Jahnke, A

AU - Wilmes, T

AU - Adebahr, S

AU - Vögtle, F-N

AU - Delima-Hahn, E

AU - Pfeifer, D

AU - Berg, T

AU - Lübbert, M

AU - Trepel, M

PY - 2007/3

Y1 - 2007/3

N2 - 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.

AB - 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.

KW - Acute Disease

KW - Aged

KW - Cell Line, Tumor

KW - Chromosomes, Human, Pair 21

KW - Chromosomes, Human, Pair 8

KW - Core Binding Factor Alpha 2 Subunit

KW - Drug Delivery Systems

KW - Drug Screening Assays, Antitumor

KW - Endocytosis

KW - Female

KW - Gene Expression Profiling

KW - Genetic Therapy

KW - Humans

KW - Integrin alpha4beta1

KW - Leukemia, Myeloid

KW - Leukemia, Myeloid, Acute

KW - Ligands

KW - Neoplasm Proteins

KW - Neoplastic Stem Cells

KW - Oligopeptides

KW - Oncogene Proteins, Fusion

KW - Peptide Library

KW - Protein Binding

KW - Receptors, Drug

KW - Translocation, Genetic

KW - Comparative Study

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/sj.leu.2404548

DO - 10.1038/sj.leu.2404548

M3 - SCORING: Journal article

C2 - 17252013

VL - 21

SP - 411

EP - 420

JO - LEUKEMIA

JF - LEUKEMIA

SN - 0887-6924

IS - 3

ER -