Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens

Katja Karjalainen; Diana E Jaalouk; Carlos Bueso-Ramos; Laura Bover; Yan Sun; Akihiko Kuniyasu; Wouter H P Driessen; Marina Cardó-Vila; Cecilia Rietz; Amado J Zurita; Susan O'Brien; Hagop M Kantarjian; Jorge E Cortes; George A Calin; Erkki Koivunen; Wadih Arap; Renata Pasqualini

doi:10.1158/1078-0432.CCR-13-3059

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Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens

Journal article

Open access

Peer reviewed

Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens

Katja Karjalainen, Diana E Jaalouk, Carlos Bueso-Ramos, Laura Bover, Yan Sun, Akihiko Kuniyasu, Wouter H P Driessen, Marina Cardó-Vila, Cecilia Rietz, Amado J Zurita, …

Clinical cancer research, Vol.21(13), pp.3041-3051

07/01/2015

DOI: https://doi.org/10.1158/1078-0432.CCR-13-3059

PMID: 25779950

Abstract

Amino Acid Sequence

Cell Survival - drug effects

Humans

Leukemia - drug therapy

Molecular Sequence Data

Receptors, Interleukin-11 - antagonists & inhibitors

Peptides - pharmacology

Lymphoma - drug therapy

Cell Line, Tumor

Inhibitory Concentration 50

Antineoplastic Agents - pharmacology

Drug Screening Assays, Antitumor

Ligands

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. 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. 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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Title: Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens
Creators: Katja Karjalainen - Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Department of Biological and Environmental Science, The University of Helsinki, Helsinki, Finland
Diana E Jaalouk - Department of Biology, American University of Beirut, Beirut, Lebanon
Carlos Bueso-Ramos - Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Laura Bover - Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Yan Sun - Department of Cancer Systems Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Akihiko Kuniyasu - Department of Molecular Cell Pharmacology, Sojo University, Kumamoto, Japan
Wouter H P Driessen - Roche, Basel, Switzerland
Marina Cardó-Vila - University of New Mexico Cancer Center, University of New Mexico School of Medicine, Albuquerque, New Mexico. Division of Molecular Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico
Cecilia Rietz - University of New Mexico Cancer Center, University of New Mexico School of Medicine, Albuquerque, New Mexico. Division of Molecular Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico
Amado J Zurita - Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Susan O'Brien - Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Hagop M Kantarjian - Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Jorge E Cortes - Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
George A Calin - Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Erkki Koivunen - Department of Biological and Environmental Science, The University of Helsinki, Helsinki, Finland. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Wadih Arap - University of New Mexico Cancer Center, University of New Mexico School of Medicine, Albuquerque, New Mexico. Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico. rpasqual@salud.unm.edu warap@salud.unm.edu
Renata Pasqualini - University of New Mexico Cancer Center, University of New Mexico School of Medicine, Albuquerque, New Mexico. Division of Molecular Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico. rpasqual@salud.unm.edu warap@salud.unm.edu
Publication Details: Clinical cancer research, Vol.21(13), pp.3041-3051
Date published: 07/01/2015
Grant note: P50 CA100632 / NCI NIH HHS
Academic Unit: Radiation Oncology; Cancer Institute of New Jersey at University Hospital
Language: English
Resource Type: Journal article
Identifiers: 991031654593104646