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DNA Methyltransferase 1 Drives Transcriptional Down‐Modulation of β Catenin Antagonist Chibby1 Associated With the BCR‐ABL1 Gene of Chronic Myeloid Leukemia
Author(s) -
Leo Elisa,
Mancini Manuela,
Castagnetti Fausto,
Gugliotta Gabriele,
Santucci Maria Alessandra,
Martinelli Giovanni
Publication year - 2015
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25010
Subject(s) - dna methylation , dna methyltransferase , dnmt1 , myeloid leukemia , biology , cancer research , methylation , epigenetics , promoter , breakpoint cluster region , methyltransferase , microbiology and biotechnology , gene , gene expression , genetics
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. J. Cell. Biochem. 116: 589–597, 2015. © 2014 Wiley Periodicals, Inc.