TY - JOUR
T1 - Targeting IL11 receptor in leukemia and lymphoma
T2 - A functional ligand-directed study and hematopathology analysis of patient-derived specimens
AU - Karjalainen, Katja
AU - Jaalouk, Diana E.
AU - Bueso-Ramos, Carlos
AU - Bover, Laura
AU - Sun, Yan
AU - Kuniyasu, Akihiko
AU - Driessen, Wouter H.P.
AU - Cardó-Vila, Marina
AU - Rietz, Cecilia
AU - Zurita, Amado J.
AU - O'Brien, Susan
AU - Kantarjian, Hagop M.
AU - Cortes, Jorge E.
AU - Calin, George A.
AU - Koivunen, Erkki
AU - Arap, Wadih
AU - Pasqualini, Renata
N1 - Publisher Copyright:
© 2014 American Association for Cancer Research.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - Purpose: The IL11 receptor (IL11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors, such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here, we evaluated the IL11R as a candidate therapeutic target in human leukemia and lymphoma. Experimental Design and Results: First, we show that the IL11R protein is expressed in a variety of human leukemia-and lymphoma-derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, whereas expression is absent from nonmalignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11), specifically bound to leukemia and lymphoma cell membranes, induced ligand-receptor internalization mediated by the IL11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analogue with an apparent improved antileukemia cell profile. Conclusions: These results indicate (i) that the IL11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases.
AB - Purpose: The IL11 receptor (IL11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors, such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here, we evaluated the IL11R as a candidate therapeutic target in human leukemia and lymphoma. Experimental Design and Results: First, we show that the IL11R protein is expressed in a variety of human leukemia-and lymphoma-derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, whereas expression is absent from nonmalignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11), specifically bound to leukemia and lymphoma cell membranes, induced ligand-receptor internalization mediated by the IL11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analogue with an apparent improved antileukemia cell profile. Conclusions: These results indicate (i) that the IL11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases.
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U2 - 10.1158/1078-0432.CCR-13-3059
DO - 10.1158/1078-0432.CCR-13-3059
M3 - Article
C2 - 25779950
AN - SCOPUS:84942249749
SN - 1078-0432
VL - 21
SP - 3041
EP - 3051
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -