Key Points: Long non-coding RNAs (lncRNAs) are molecules that normally regulate cellular functions. The activation of lncRNAs can play important roles in cancer development. This study identified the role of a particular lncRNA in a type of acute leukemia and showed that blocking the molecule could offer a new treatment for the disease. COLUMBUS, Ohio – A new study led by researchers at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James) has identified a molecule that promotes rapid growth and proliferation of leukemic cells by regulating protein synthesis. The molecule is a type called long non-coding RNAs (lncRNAs), which are ribbon-like molecules more than 200 building blocks (nucleotides) long. Normally, the molecules play important roles in regulating cell activity during embryonic development, but their abnormal activation later in life can significantly contribute to cancer development. In this study, researchers examined the role of a lncRNA called HOXB-AS3 in a type of acute myeloid leukemia (AML) that carries a common genetic mutation called nucleophosmin (NPM1-mutated AML). The researchers found that abnormally high levels of HOXB-AS3 in the leukemic cells of people with NPM1-mutated AML can supercharge the rate of protein synthesis, enabling the rapid growth and proliferation of malignant blast (immature) cells. The study further suggests that targeting HOXB-AS3 might lead to new and less toxic treatments for people with NPM1-mutated AML. The findings are reported in the journal Nature Communications. “HOXB-AS3 is one of the most highly upregulated lncRNAs in this type of leukemia,” says principal investigator Ramiro Garzon, MD, professor in Ohio State's Division of Hematology and co-leader of the Leukemia Research Program at the OSUCCC – James. “Our findings show that NPM1 gene mutations drive the upregulation of HOXB-AS3 and that depleting HOXB-AS3 has an anti-leukemic effect. This is a very hopeful discovery because novel therapies for the treatment of acute myeloid leukemia are urgently needed. This opens up a new avenue to treat a very frequent type of AML with a targeted therapy that could help our patients without the toxicity associated with standard chemotherapy.” Although additional research is needed, the researchers say their findings suggest that blocking HOXB-AS3 would be feasible and offer a new treatment for NPM1-AML. “To our knowledge, our preclinical model is one of the few to show that targeting a long non-coding RNA alone can produce therapeutic results,” says co-author Clara D. Bloomfield, MD, a Distinguished University Professor at Ohio State who also serves as cancer scholar and senior adviser to the OSUCCC – James. For this study, Garzon, Bloomfield and their colleagues examined blast cells and healthy cells from patients with NPM1-mutated AML. They also used animal models to determine the function of HOXB-AS3 and to show that targeting the molecule might offer a new treatment for the disease. Key findings include: HOXB-AS3 overexpression is driven by NPM1 mutations. HOXB-AS3 regulates ribosomal RNA transcription and protein synthesis. Knocking down HOXB-AS3 in leukemic blast cells decreased their rate of proliferation, while its overexpression increased leukemic cell proliferation. Knockdown of HOXB-AS3 in an animal model prolonged the survival of treated mice. This study was supported by grants from the U.S. National Institute of Health/National Cancer Institute (CA233338, CA196171 and CA180861), the Lundbeck Foundation (R151-2013-14476) and the Novo Nordisk Foundation (NNF13OC0006395). Other researchers involved in this study were Dimitrios Papaioannou, Frances A. Collins, Lauren A. Woodward, Allison E. Walker, Deedra Nicolet, Felice Pepe, Prasanthi Kumchala, Marius Bill, Christopher J. Walker, Malith Karunasiri, Krzysztof Mrózek, Miranda Gardner, Nina Zitzer, Xiaoqing Rong-Mullins, Jessica Kohlschmidt, Kellie J. Archer, Guramrit Singh and Adrienne M. Dorrance, The Ohio State University; Andreas Petri and Sakari Kauppinen, Aalborg University, Copenhagen, Denmark; Oliver M. Dovey and Jonathan L. Cooper, Wellcome Trust Sanger Institute, Cambridge, UK; Sara Terreri, National Council of Research (CNR), Naples, Italy; Eric Wang and Iannis Aifantis, New York University School of Medicine; Virginia Camilotto, University of Pavia, Pavia, Italy; Xiongwei Cai and Yi Zheng, University of Cincinnati; Robert J. Lee, University of Ferrara, Ferrara, Italy; George Vassiliou Cambridge University Hospitals NHS Trust, Cambridge, UK. About the OSUCCC – James The OSUCCC – James 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 51 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only a few centers funded by the NCI to conduct both phase I and phase II clinical trials on novel anticancer drugs sponsored by the NCI. As the cancer program’s 356-bed adult patient-care component, The James is one of the top cancer hospitals in the nation as ranked by U.S. News & World Report and has achieved Magnet® designation, the highest honor an organization can receive for quality patient care and professional nursing practice. At 21 floors and with more than 1.1 million square feet, The James is a transformational facility that fosters collaboration and integration of cancer research and clinical cancer care. For more information, visit cancer.osu.edu Media Contact: Amanda J. Harper OSUCCC – James Media Relations Direct Line: 614-685-5420 Central Media Relations: 614-293-3737 Amanda.Harper2@osumc.edu