Figure 7.

Proposed mechanism of CLIC5A involvement in ETV6-associated childhood pre-B ALL. The t(12;21) translocation occurs early and contributes to an increased level of reactive oxygen species (ROS). Lysosome-mediated apoptosis is sensitive to this excess of ROS and therefore prevents the accumulation of ROS-mediated DNA damage. With the subsequent deletion of the residual ETV6 allele (LOH), CLIC5A expression is drastically upregulated. This overexpression of CLIC5A has a negative impact on the lysosomal apoptosis pathway and thus creates a permissive environment for the accumulation of mutations driven by high oxidative stress. Over time, some of these mutations may impact key cellular biological processes and pathways, which will ultimately lead to full leukemic transformation and development of childhood pre-B acute lymphoblastic leukemia (pre-B ALL).