“By using the expertise of multiple labs we’ve been able to identify how the mutant protein RBM15-MKL1 interacts with RNA on a very deep level, and we’ve shown that these interactions are essential for how leukemia persists. This is a huge step forward in understanding this disease,” says doctoral student Madeline Mayday, a primary author on the study and a member of the Krause Lab at Yale Cancer Center.
The study found that the mutant protein selectively regulates Frizzled proteins, which are linked to activation of a known cancer pathway called Wnt signaling. Inhibition of Frizzled gene activity hampered the growth of AMKL in the lab and in animals, highlighting the role of Wnt signaling in this specific blood cancer.
“We looked at hundreds of patient samples across many types of leukemia and saw that AMKL caused by other genetic alterations also had upregulation of a Wnt pathway signature suggesting that all forms of AMKL may have evolved with a common reliance on Wnt signaling and may thus be targetable with drugs that target the Wnt pathway,” says Diane Krause, MD, PhD, a senior author on the study and Anthony N. Brady Professor of Laboratory Medicine and professor of pathology at Yale School of Medicine.
The researchers also showed that an experimental inhibitor of the m6A process—a drug called STM3675 that has been used in pre-clinical studies—disrupts m6A modification, decreases pathways such as Wnt signaling, and kills leukemia cells in the lab and in mice.
“Our study highlights the importance of translational research. We developed AMKL preclinical models to investigate RNA binding and m6A alterations that are driven by a leukemogenic mutant protein, and we showed that these alterations can be corrected when using a small molecule inhibitor with demonstrated anti-cancer activity,” says Giulia Biancon, PhD, primary and co-corresponding author and a former member of the Halene Lab at Yale Cancer Center.
“This discovery provides further evidence of how alterations in RNA biology drive human diseases and demonstrates the power of big data analysis in uncovering these crucial mechanisms,” says Toma Tebaldi, PhD, a senior author on the study and an adjunct assistant professor of medicine (medical oncology and hematology).
Arthur H and Isabel Bunker Professor of Medicine (Hematology) and Professor of Pathology Stephanie Halene, MD, a senior author on the study says that drugs targeting both the writer of the m6A modification and the Wnt pathway are in clinical trials for cancer and could one day be available to treat this rare leukemia in children.
The research reported in this news article was supported by the Lo Graduate Fellowship for Excellence in Stem Cell Research, the Yale Cooperative Center of Excellence in Hematology (NIDDK U54DK106857), the American Society of Hematology, the Edward P. Evans Foundation, the DeLuca Center for Innovation in Hematology Research at Yale Cancer Center, the AIRC Foundation for Cancer Research , the Leukemia and Lymphoma Society, the National Recovery and Resilience Plan, the European Union and the Italian Ministry of Education, University, and Research, the National Institutes of Health (awards F31CA27157, T32HL007974, R01GM137117, R01CA222518, R01CA253981, 1R01CA266604, and RC2DK122376), and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.