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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of
Katja Karjalainen1, Diana E Jaalouk2, Carlos Bueso-Ramos3
1Department 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.
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.
Insights
The Interleukin-11 receptor (IL11R) is expressed in leukemia and lymphoma cells but not in healthy bone marrow. A novel therapeutic agent, BMTP-11, targets IL11R, inducing cancer cell death and showing promise for treating these blood cancers.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- The Interleukin-11 receptor (IL11R) is a validated target for bone cancers like osteosarcoma and bone metastases from prostate cancer.
- Its role in hematopoietic malignancies, including leukemia and lymphoma, remains largely unexplored.
Purpose of the Study:
- To investigate the IL11R as a potential therapeutic target in human leukemia and lymphoma.
- To assess the expression of IL11R in malignant hematopoietic cells and nonmalignant controls.
Main Methods:
- Analysis of IL11R protein expression in leukemia and lymphoma cell lines and patient bone marrow samples.
- Utilizing a peptidomimetic prototype (BMTP-11) designed to bind IL11R on cancer cell membranes.
- Evaluating the induction of ligand-receptor internalization and subsequent cell death by BMTP-11.
- Conducting a drug lead-optimization program to develop improved analogues.
Main Results:
- IL11R protein was detected in various human leukemia and lymphoma cell lines and patient samples.
- IL11R expression was notably absent in nonmalignant bone marrow samples.
- BMTP-11 demonstrated specific binding to leukemia and lymphoma cells, inducing IL11R-mediated internalization.
- BMTP-11 triggered dose-dependent cell death in malignant hematopoietic cells.
- An optimized myristoylated BMTP-11 analogue showed an enhanced anti-leukemia cell profile.
Conclusions:
- The IL11R is a viable cell surface target for targeted therapies in human leukemia and lymphoma.
- BMTP-11 and its derivatives exhibit significant translational potential for treating these hematologic malignancies.
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