TY - JOUR
T1 - Targeting neuropilin-1 in human leukemia and lymphoma
AU - Karjalainen, Katja
AU - Jaalouk, Diana E.
AU - Bueso-Ramos, Carlos E.
AU - Zurita, Amado J.
AU - Kuniyasu, Akihiko
AU - Eckhardt, Bedrich L.
AU - Marini, Frank C.
AU - Lichtiger, Benjamin
AU - O'Brien, Susan
AU - Kantarjian, Hagop M.
AU - Cortes, Jorge E.
AU - Koivunen, Erkki
AU - Arap, Wadih
AU - Pasqualini, Renata
PY - 2011/1/20
Y1 - 2011/1/20
N2 - Targeted drug delivery offers an opportunity for the development of safer and more effective therapies for the treatment of cancer. In this study, we sought to identify short, cell-internalizing peptide ligands that could serve as directive agents for specific drug delivery in hematologic malignancies. By screening of human leukemia cells with a combinatorial phage display peptide library, we isolated a peptide motif, sequence Phe-Phe/Tyr-Any-Leu-Arg-Ser (FF/YXLRS), which bound to different leukemia cell lines and to patient-derived bone marrow samples. The motif was internalized through a receptor-mediated pathway, and we next identified the corresponding receptor as the transmembrane glycoprotein neuropilin-1 (NRP-1). Moreover, we observed a potent anti-leukemia cell effect when the targeting motif was synthesized in tandem to the pro-apoptotic sequence D(KLAKLAK)2. Finally, our results confirmed increased expression of NRP-1 in representative human leukemia and lymphoma cell lines and in a panel of bone marrow specimens obtained from patients with acute lymphoblastic leukemia or acute myelogenous leukemia compared with normal bone marrow. These results indicate that NRP-1 could potentially be used as a target for liganddirected therapy in human leukemias and lymphomas and that the prototype CGFYWLRSC-GG- D(KLAKLAK)2 is a promising drug candidate in this setting.
AB - Targeted drug delivery offers an opportunity for the development of safer and more effective therapies for the treatment of cancer. In this study, we sought to identify short, cell-internalizing peptide ligands that could serve as directive agents for specific drug delivery in hematologic malignancies. By screening of human leukemia cells with a combinatorial phage display peptide library, we isolated a peptide motif, sequence Phe-Phe/Tyr-Any-Leu-Arg-Ser (FF/YXLRS), which bound to different leukemia cell lines and to patient-derived bone marrow samples. The motif was internalized through a receptor-mediated pathway, and we next identified the corresponding receptor as the transmembrane glycoprotein neuropilin-1 (NRP-1). Moreover, we observed a potent anti-leukemia cell effect when the targeting motif was synthesized in tandem to the pro-apoptotic sequence D(KLAKLAK)2. Finally, our results confirmed increased expression of NRP-1 in representative human leukemia and lymphoma cell lines and in a panel of bone marrow specimens obtained from patients with acute lymphoblastic leukemia or acute myelogenous leukemia compared with normal bone marrow. These results indicate that NRP-1 could potentially be used as a target for liganddirected therapy in human leukemias and lymphomas and that the prototype CGFYWLRSC-GG- D(KLAKLAK)2 is a promising drug candidate in this setting.
UR - http://www.scopus.com/inward/record.url?scp=78751687553&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78751687553&partnerID=8YFLogxK
U2 - 10.1182/blood-2010-05-282921
DO - 10.1182/blood-2010-05-282921
M3 - Article
C2 - 21063027
AN - SCOPUS:78751687553
SN - 0006-4971
VL - 117
SP - 920
EP - 927
JO - Blood
JF - Blood
IS - 3
ER -
