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Title: Effects of TET2 mutations on DNA methylation in chronic myelomonocytic leukemia

item YAMAZAKI, JUMPEI - Md Anderson Cancer Center
item TABY, RODOLPHE - Md Anderson Cancer Center
item VASANTHAKUMAR, APARNA - University Of Chicago
item MACRAE, TRISHA - University Of Chicago
item OSTLER, KELLY - University Of Chicago
item SHEN, LANLAN - Children'S Nutrition Research Center (CNRC)
item KANTARJIAN, HAGOP - Md Anderson Cancer Center
item ESTECIO, MARCOS - Md Anderson Cancer Center
item JELINEK, JAROSLAV - Md Anderson Cancer Center
item GODLEY, LUCY - University Of Chicago
item ISSA, JEAN-PIERRE - Md Anderson Cancer Center

Submitted to: Epigenetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/12/2011
Publication Date: 2/1/2012
Citation: Yamazaki, J., Taby, R., Vasanthakumar, A., Macrae, T., Ostler, K.R., Shen, L., Kantarjian, H.M., Estecio, M.R., Jelinek, J., Godley, L.A., Issa, J.J. 2012. Effects of TET2 mutations on DNA methylation in chronic myelomonocytic leukemia. Epigenetics. 7(2):201-207.

Interpretive Summary: Abnormal DNA methylation (a type of chemical modification of DNA that changes gene expression potential) is the most common molecular lesion of the cancer cell. In particular, genes that help prevent cancer are frequently inactivated by abnormally increased methylation at key regulatory regions (i.e., promoters). The cause of such aberrant DNA methylation in cancer, however, remains largely unknown. This research seeks to understand whether increased DNA methylation in cancer is caused by mutations at a gene (TET2) that regulates DNA methylation reactions. By comparing leukemia patients with or without this gene mutation, we found that there is no difference in the frequency of abnormal gene methylation. Our research provides important insights into both genetic and epigenetic processes during cancer development.

Technical Abstract: TET2 enzymatically converts 5-methyl-cytosine to 5-hydroxymethyl-cytosine, possibly leading to loss of DNA methylation. TET2 mutations are common in myeloid leukemia and were proposed to contribute to leukemogenesis through DNA methylation. To expand on this concept, we studied chronic myelomonocytic leukemia (CMML) samples. TET2 missense or nonsense mutations were detected in 53% (16/30) of patients. In contrast, only 1/30 patients had a mutation in IDH1 or IDH2, and none of them had a mutation in DNMT3A in the sites most frequently mutated in leukemia. Using bisulfite pyrosequencing, global methylation measured by the LINE-1 assay and DNA methylation levels of 10 promoter CpG islands frequently abnormal in myeloid leukemia were not different between TET2 mutants and wild-type CMML cases. This was also true for 9 out of 11 gene promoters reported by others as differentially methylated by TET2 mutations. We found that two non-CpG island promoters, AIM2 and SP140, were hypermethylated in patients with mutant TET2. These were the only two gene promoters (out of 14,475 genes) previously found to be hypermethylated in TET2 mutant cases. However, total 5-methyl-cytosine levels in TET2 mutant cases were significantly higher than TET2 wild-type cases (median = 14.0% and 9.8%, respectively) (p = 0.016). Thus, TET2 mutations affect global methylation in CMML but most of the changes are likely to be outside gene promoters.