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.
Dipartimento di Medicina Specialistica, Diagnostica a Sperimentale-DIMES, Istituto di Ematologia "L. e A. Seràgnoli" - University of Bologna - Medical School, Bologna, Italy.
Elisa
E
Leo
Manuela
M
Mancini
Fausto
F
Castagnetti
Gabriele
G
Gugliotta
Maria Alessandra
MA
Santucci
Giovanni
G
Martinelli
D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051176:beta Catenin / Q000037:antagonists & inhibitors
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C473750:CBY1 protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D051176:beta Catenin; D000068877:Imatinib Mesylate; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D016044:Fusion Proteins, bcr-abl
BCL2-LIKE11; BCR-ABL1; CHIBBY1; CHRONIC MYELOID LEUKEMIA; DNA METHYLTRANSFERASE 1