Breakthrough in Targeted Therapy for Rare and Aggressive Leukemia

Researchers from Yale University have uncovered a promising new pathway that could lead to effective treatments for a rare and highly aggressive form of leukemia known as acute megakaryoblastic leukemia (AMKL). Published in the journal Blood, the study focuses on understanding the genetic and molecular mechanisms driving this leukemia, particularly those linked to specific genetic alterations primarily seen in pediatric patients.

The key discovery involves a fusion protein called RBM15-MKL1, which forms due to a unique genetic change. This mutant protein interferes with RNA modification processes, specifically m6A methylation, disrupting normal gene regulation. By hijacking these RNA processes, the fusion protein sustains leukemia cell growth. Furthermore, the study reveals that this mutant protein influences the activity of Frizzled proteins, which activate the Wnt signaling pathway, known to promote cancer development.

Laboratory experiments demonstrated that inhibiting Frizzled proteins could slow down or halt leukemia growth, suggesting the Wnt pathway as a potential therapeutic target. The researchers also tested an experimental drug, STM3675, that blocks m6A modification, which successfully reduced leukemia cell proliferation in both cell cultures and mouse models. These findings point toward a new approach to treating AMKL by targeting key genetic and RNA-modifying processes.

Senior author Dr. Diane Krause emphasized that all forms of AMKL may rely on the Wnt signaling pathway, which opens the door for drugs targeting this pathway. As the study progresses, certain inhibitors currently in clinical trials may become viable options for treating this deadly leukemia in children, offering hope for better outcomes.

This research exemplifies the importance of translational medicine, bridging laboratory discoveries with potential clinical applications. By unraveling how genetic mutations influence RNA biology and leveraging big data analysis, scientists are paving the way for novel targeted therapies against leukemia.