Paradoxical enhancement of leukemogenesis in acute myeloid leukemia with moderately attenuated RUNX1 expressions.

Besides being a classical tumor suppressor, runt-related transcription factor 1 (RUNX1) is now widely recognized for its oncogenic role in the development of acute myeloid leukemia (AML). Here we report that this bidirectional function of RUNX1 possibly arises from the total level of RUNX family expressions. Indeed, analysis of clinical data revealed that intermediate-level gene expression of marked the poorest-prognostic cohort in relation to AML patients with high- or low-level expressions. Through a series of knockdown experiments with various attenuation potentials, we found that moderate attenuation of contributed to the enhanced propagation of AML cells through accelerated cell-cycle progression, whereas profound depletion led to cell-cycle arrest and apoptosis. In these -silenced tumors, amounts of compensative upregulation of and expressions were roughly equivalent and created an absolute elevation of total ( + + ) expression levels in moderately attenuated AML cells. This elevation resulted in enhanced transactivation of glutathione -transferase α 2 (GSTA2) expression, a vital enzyme handling the catabolization of intracellular reactive oxygen species (ROS) as well as advancing the cell-cycle progressions, and thus ultimately led to the acquisition of proliferative advantage in moderately attenuated AML cells. Besides, treatment with ethacrynic acid, which is known for its GSTA inhibiting property, actually prolonged the survival of AML mice in vivo. Collectively, our findings indicate that moderately attenuated expressions paradoxically enhance leukemogenesis in AML cells through intracellular environmental change via GSTA2, which could be a novel therapeutic target in antileukemia strategy.