CLIC5: a novel ETV6 target gene in childhood acute lymphoblastic leukemia

The most common rearrangement in childhood precursor B-cell acute lymphoblastic leukemia is the t(12; 21)(p13; q22) translocation resul-ting in the ETV6-AML1 fusion gene. A frequent concomitant event is the loss of the residual ETV6 allele suggesting a critical role for the ETV6 transcriptional repressor in the etiology of this cancer. However, the precise mechanism through which loss of functional ETV6 contributes to disease pathogenesis is still unclear. To investigate the impact of ETV6 loss on the transcriptional network and to identify new transcriptional targets of ETV6, we used whole transcriptome analysis of both pre-B leukemic cell lines and patients combined with chromatin immunoprecipitation. Using this integrative approach, we identified 4 novel direct ETV6 target genes: CLIC5, BIRC7, ANGPTL2 and WBP1L. To further evaluate the role of chloride intracellular channel protein CLIC5 in leukemogenesis, we generated cell lines overexpressing CLIC5 and demonstrated an increased resistance to hydrogen peroxide-induced apoptosis. We further described the implications of CLIC5's ion channel activity in lysosomal-mediated cell death, possibly by modulating the function of the transferrin receptor with which it colocal-izes intracellularly. For the first time, we showed that loss of ETV6 leads to significant overexpression of CLIC5, which in turn leads to decreased lysosome-mediated apoptosis. Our data suggest that heightened CLIC5 activity could promote a permissive environment for oxidative stress-induced DNA damage accumulation, and thereby contribute to leukemogenesis.