Aggressive Leukemia Triggered by Unexpected Source

  • A protein previously known as a tumor suppressor might actually cause leukemia to become more aggressive, according to researchers from Cincinnati Children’s Hospital Medical Center.


    The preponderance of evidence shows that this protein, known as RUNX1, can contribute to the formation and growth of tumors. New research now suggests that blocking this protein normally credited with suppressing leukemia may be a promising therapeutic strategy for cancer patients.


    The new study, published online by the Journal of Clinical Investigation, specifically examines the protein’s role in Acute Myeloid Leukemia (AML)—the most common acute leukemia affecting adults and also the most common type of leukemia diagnosed during infancy.

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    This subtype of leukemia blocks the production of normal cells and lowers the number of healthy blood cells, including red cells, white cells and platelets. AML can be caused in part by genetic disorders and chemotherapy or radiation therapy for other cancers or by the progression of other blood cancers. Experts say it remains one of the most difficult cancers to treat.


    Until recently, studies that have indicated that RUNX1 is a tumor suppressor have not made it clear how its properties exactly relate to the regulation of blood cell development. One study from the Milne group, published earlier this year in Cancer Reports, showed that the protein can, in fact, act as an essential factor in acute leukemia. James Mulloy PhD., lead investigator and a researcher in the Division of Experimental Hematology and Cancer Biology at Cincinnati Children’s Hospital Medical Center, said he thinks that this study, combined with his recent findings, confirms that the protein RUNX1 does play a critical role in human leukemia.


    In the new study, Mulloy and the team of researchers took these previous studies a step further to find out if the protein under study could potentially serve as a therapeutic target.


    Researchers studied the effects of inhibiting the protein in both human AML samples and a genetically engineered mouse model. In the human samples, researchers removed the protein. In the mouse model, researchers deleted a certain gene from the cells, which made it impossible for the cells to make the protein. “All approaches led to the same conclusion, that expression of (RUNX) protein is important to the survival of the AML cells,” said Mulloy.


    Although differences exist between mouse models and clinical diseases, mouse models have proven to be invaluable tools for the understanding of human cancer. The genetically-engineered mouse model used in this study provided one of the best representations of human disease, according to William C. Phelps, PhD, Director of Preclinical and Translational Cancer Research at the American Cancer Society.


    It is important to note that this study was not a clinical trial—that is, it was not a rigorously controlled test on human subjects. New drugs or invasive medical devices in the United States must be conducted under the direction of the U.S. Food and Drug Administration (FDA) before being made available for general clinical use.


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    Researchers said that clinical trials would be essential before this approach becomes accepted as a standard treatment for patients. Until the new targeting strategy is proven in clinical trials, nothing will change with regard to current standard care. This process can be lengthy and take up to 20 years for the FDA to approve trials to move from pre-clinical to clinical, although researchers said they think this process will take less time than that.


    While this study focused on a particular subtype of AML that only accounts for about 5-10 percent of human AML cases, it did not rule out the possibility that the approach of inhibiting the RUNX1 protein could be useful for other subtypes of AML. This cannot be concluded with certainty, however, until results of clinical trials are known.


    With this pre-clinical trial, along with other various trials in this area of cancer research, the FDA must be concerned about both the effectiveness and potential consequences of innovative leukemia therapies. One challenge is developing treatments that cure patients of all ages and with all types of AML. Relapse is also a major concern for AML patients, as more than half of the patients who achieve complete remission under current therapies are predicted to have a relapse, according to a 2001 study published in Blood.


    “These new findings could help researchers understand why some patients relapse and why others don’t,” said Phelps.


    The research team at Cincinnati’s said they are going to continue testing using the protein-inhibitor in AML therapy and in other related blood disorders. Their ultimate goal is to see how their findings might eventually lead to potential treatment of human disease.


    In the best-case scenario, these new findings could help researchers develop effective RUNX1-inhibitors and patient therapies that are more effective and have fewer side effects than those of current standard therapies. “While this is a pre-clinical study using a lead compound that is not ready for clinical trial, the potential is clear,” said Mulloy. “Targeting RUNX1 shows efficacy in our pre-clinical studies, including in studies using primary human AML patient samples,” he said.


    Phelps said the study’s findings could help provide insight into other current drug developments and could help inform developments in other types of cancer, such as breast, skin and lung cancer.



    Goyama, Susumu, Janet Schibler, Lea Cunningham, Yue Zhang, Yalan Rao, Nahoko Nishimoto, Masahiro Nakagawa, Andre Olsson, Mark Wunderlich, Kevin A. Link, Benjamin Mizukawa, Leighton H. Grimes, Mineo Kurokawa, Paul P. Liu, Gang Huang, and James C. Mulloy. "Transcription Factor RUNX1 Promotes Survival of Acute Myeloid Leukemia Cells." Journal of Clinical Investigation, 27 Aug. 2013. Web. 03 Sept. 2013. <>.

Published On: September 04, 2013