Production and Characterization of K562 Cellular Clones Hyper-Expressing the Gene Encoding α-Globin: Preliminary Analysis of Biomarkers Associated with Autophagy

One of the most relevant pathophysiological hallmarks of beta-thalassemia is the accumulation of toxic alpha-globin chains inside erythroid cells, which is responsible for their premature death (hemolysis). In this context, the availability of an experimental model system mimicking the excess in alpha-globin chain production is still lacking. The objective of the present study was to produce and characterize K562 cellular clones forced to produce high amounts of alpha-globin, in order to develop an experimental model system suitable for studies aimed at the reduction of the accumulation of toxic alpha-globin aggregates. In the present study, we produced and characterized K562 cellular clones that, unlike the original K562 cell line, stably produced high levels of alpha-globin protein. As expected, the obtained clones had a tendency to undergo apoptosis that was proportional to the accumulation of alpha-globin, confirming the pivotal role of alpha-globin accumulation in damaging erythroid cells. Interestingly, the obtained clones seemed to trigger autophagy spontaneously, probably to overcome the accumulation/toxicity of the alpha-globin. We propose this new model system for the screening of pharmacological agents able to activate the full program of autophagy to reduce alpha-globin accumulation, but the model may be also suitable for new therapeutical approaches targeted at the reduction of the expression of the alpha-globin gene.

Automated summary

The objective of this study was to develop an experimental model system for studying the reduction of toxic alpha-globin aggregates in beta-thalassemia. K562 cellular clones were produced that stably produced high levels of alpha-globin protein and showed increased apoptosis and autophagy. This model system can be used to screen pharmacological agents that activate autophagy and reduce alpha-globin accumulation, as well as for new therapeutic approaches targeting the reduction of alpha-globin gene expression.