The study shows that high levels of interleukin-15 (IL-15) alone can cause large granular lymphocytic (LGL) leukemia, a rare and usually fatal form of cancer, in an animal model. The researchers also developed a treatment for the leukemia that showed no discernible side effects in the animal model.
Published in the journal Cancer Cell, the findings show that IL-15 is also overexpressed in patients with LGL leukemia and that it causes similar cellular changes, suggesting that the treatment should also benefit people with the malignancy.
“We know that inflammation can cause cancer, but we don’t know the exact mechanism,” says the study’s co-senior author Dr. Michael A. Caligiuri, CEO of The James Cancer Hospital and Solove Research Institute, and director of Ohio State’s Comprehensive Cancer Center.
“Here, we show one way it can happen, and we used that information to potentially cure the cancer.”
The research was developed and carried out in collaboration with co-senior author Dr. Guido Marcucci, associate director for Translational Research at the OSUCCC – James.
“In this study, we show the joined role of genetic instability and microRNAs in leading directly to cancer,” says Marcucci, who notes that this work is part of a long history of research at OSUCCC revealing the role of microRNA in cancer and its potential as a therapeutic target.
Normally, the body releases IL-15 to stimulate the development, survival and proliferation of natural-killer cells, which are immune cells that destroy cancer and virus-infected cells. This research shows that when IL-15 is present in high amounts in the body for prolonged periods, such as during chronic inflammation, it can cause certain immune cells called large granular lymphocytes, or LGLs, to become cancerous.
This malignant transformation begins when IL-15 attaches to receptors on the surface of normal LGLs, an event that boosts levels of a cancer-causing protein called Myc (pronounced “mick”) inside the cells. The high Myc levels, in turn, bring changes that cause chromosome instability and additional gene mutations. The high Myc levels also activate a process called DNA methylation, which turns off a variety of genes, including important genes that normally suppress cancer growth.
“We stand the best chance of curing cancer when we understand its causes,” says first author Anjali Mishra, a postdoctoral researcher in Caligiuri’s laboratory. “Once we understood how this inflammatory hormone causes this leukemia, we used that information to develop a treatment by interfering with the process.”
Caligiuri, Marcucci and Mishra were joined in this study by Dr. Robert Lee, professor of pharmaceutics and pharmaceutical chemistry in Ohio State’s College of Pharmacy and a group of collaborators. The investigators conducted the research using cells isolated from patients with LGL leukemia and a mouse model of the disease. Key findings include:
Exposing normal, human, large granular lymphocytes to IL-15 caused cell proliferation, chromosomal instability and global DNA hypermethylation;
Excessive IL-15 activated the cancer-causing Myc oncogene in large granular lymphocytes, leading to genetic instability, DNA hypermethylation and malignant transformation;
Details of how Myc upregulation causes the genetic instability and hypermethylation.
Lee developed a liposomal formulation of the proteosome inhibitor bortezomib that shuts down the cancer-causing pathway, potentially curing the malignancy. Leukemic mice treated with the liposomal bortezomib showed 100 percent survival at 130 days versus 100 percent mortality at 60-80 days for control animals.
“We now plan to develop this drug for clinical use,” says Marcucci, who holds the John B. and Jane T. McCoy Chair in Cancer Research in Cancer Research.
Funding from the NIH/National Cancer Institute (grants CA16058, CA95426, CA68458, CA09338, CA140158, CA102031 and CA149623) and the National Science Foundation (grant EEC-0914790) supported this research.
Other Ohio State researchers involved in this study were Shujun Liu, Gregory H. Sams, Douglas P. Curphey, Ramasamy Santhanam, Laura J. Rush, Deanna Schaefer, Lauren G. Falkenberg, Laura Sullivan, Laura Jaroncyk, Xiaojuan Yang, Harold Fisk, Lai-Chu Wu, Christopher Hickey, Jason C. Chandler, Yue-Zhong Wu, Nyla A. Heerema, Kenneth K. Chan, Danilo Perrotti, Jianying Zhang, Pierluigi Porcu, Frederick K. Racke and Ramiro Garzon.
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only seven centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State’s cancer program as “exceptional,” the highest rating given by NCI survey teams. As the cancer program’s 228-bed adult patient-care component, The James is a “Top Hospital” as named by the Leapfrog Group and one of the top cancer hospitals in the nation as ranked by
U.S.News & World Report.
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