DNA methyltransferase 1 drives transcriptional down-modulation of β catenin antagonist Chibby1 associated with the BCR-ABL1 gene of chronic myeloid leukemia.

The decrease of Chibby1 (CBY1) contributes to β catenin constitutive activation associated with the presence of the BCR-ABL1 fusion gene of chronic myeloid leukemia (CML). This is mediated by transcriptional events and driven by DNA hyper-methylation at promoter-associated CpG islands of the CBY1-encoding gene C22orf2. Moreover, CBY1 transcriptional induction proceeding from promoter de-methylation is a component of BCR-ABL1+ cell response to Imatinib (IM). Our study showed that DNA methyltransferase 1 (DNMT1) has a central role in the hyper-methylation at the C22orf2 promoter. Further investigation in leukemic hematopoietic progenitors from IM-responsive and IM-resistant CML patients at diagnosis failed to demonstrate any correlation between DNMT1-driven hyper-methylation of the C22orf2 promoter and response to IM. Notably, the response to IM was neither predicted by DNMT1-driven hyper-methylation of BCL2-like11 at diagnosis. In conclusion, the hypermethylation of C22orf2 and BCL2-like11 promoters proceeding from DNMT1 is a crucial component of their reduced expression, but it is not directly involved in CML resistance to IM. It might rather contribute to the disease evolution towards a drug-resistant phenotype in more advanced phases or blast crisis.