ENOX2 NADH Oxidase: A BCR-ABL1-dependent Cell Surface and Secreted Redox Protein in Chronic Myeloid Leukemia (CML)

Seda Baykal, Maud Voldoire, Christophe Desterke, Nathalie Sorel, Emilie Cayssials, Hyacinthe Johnson-Ansah, Agnes Guerci-Bresler, Annelise Bennaceur-Griscelli, Jean-Claude Chomel, Ali G. Turhan

Chronic myeloid leukemia (CML) is a disease caused by the acquisition of BCR-ABL1 fusion in a hematopoietic stem cell. In this study, we focused on the oncofoetal ENOX2 protein as a potential secretable biomarker in CML. We used cell culture, Western blot, quantitative RT-PCR, ELISA, transcriptome analyses and bioinformatics technics to investigate ENOX2 mRNA and protein expression. Western-blot analyses on UT-7 and TET-inducible Ba/F3 cell lines demonstrated the up-regulation of ENOX2 protein. BCR-ABL1 has been found to induce ENOX2 overexpression in a kinase-dependent manner. We confirmed increased ENOX2 mRNA expression on a cohort of CML patients at diagnosis. In a series of CML patients, ELISA assays showed a highly significant increase of ENOX2 protein levels in the plasma of patients with CML compared to controls. Transcriptomic dataset reanalyzes confirmed ENOX2 mRNA overexpression in the chronic phase of the disease. Bioinformatic analyses identified several genes whose mRNA expression was positively correlated to ENOX2 in a BCR-ABL1 context. Some of them encode proteins involved in cellular functions compatible with the growth deregulation observed in CML. Our results highlight the upregulation of a secreted Redox protein in a BCR-ABL1-dependent manner in CML. Our data suggest that ENOX2, through its transcriptional program, plays a significant role in BCR-ABL1 leukemogenesis.