DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia Journal Article
| Authors: | Rampal, R.; Alkalin, A.; Madzo, J.; Vasanthakumar, A.; Pronier, E.; Patel, J.; Li, Y.; Ahn, J.; Abdel-Wahab, O.; Shih, A.; Lu, C.; Ward, P. S.; Tsai, J. J.; Hricik, T.; Tosello, V.; Tallman, J. E.; Zhao, X.; Daniels, D.; Dai, Q.; Ciminio, L.; Aifantis, I.; He, C.; Fuks, F.; Tallman, M. S.; Ferrando, A.; Nimer, S.; Paietta, E.; Thompson, C. B.; Licht, J. D.; Mason, C. E.; Godley, L. A.; Melnick, A.; Figueroa, M. E.; Levine, R. L. |
| Article Title: | DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia |
| Abstract: | Somatic mutations in IDH1/IDH2 and TET2 result in impaired TET2-mediated conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). The observation that WT1 inactivating mutations anticorrelate with TET2/IDH1/IDH2 mutations in acute myeloid leukemia (AML) led us to hypothesize that WT1 mutations may impact TET2 function. WT1 mutant AML patients have reduced 5hmC levels similar to TET2/IDH1/IDH2 mutant AML. These mutations are characterized by convergent, site-specific alterations in DNA hydroxymethylation, which drive differential gene expression more than alterations inDNA promoter methylation. WT1 overexpression increases global levels of 5hmC, and WT1 silencing reduced 5hmC levels. WT1 physically interacts with TET2 and TET3, and WT1 loss of function results in a similar hematopoietic differentiation phenotype as observed with TET2 deficiency. These data provide a role for WT1 in regulating DNA hydroxymethylation and suggest that TET2 IDH1/IDH2 and WT1 mutations define an AML subtype defined by dysregulated DNA hydroxymethylation. Mutational studies in patients with acute myeloid leukemia (AML) have identified recurrent mutations in TET2 and IDH1/IDH2, and these mutations result in a reduction in 5-hydroxymethylcytosine (5hmC) levels. Rampal etal. demonstrate that WT1 mutations anticorrelate with TET2 and IDH1/IDH2 mutations, and WT1 mutant AMLs have decreased 5hmC levels, consistent with reduced TET2 function. |
| Keywords: | controlled study; acute granulocytic leukemia; gene mutation; major clinical study; promoter region; nonhuman; animal cell; mouse; gene; complex formation; gene expression; dna methylation; hematopoietic cell; wt1 protein; loss of function mutation; tet2 gene; clinical trial (topic); isocitrate dehydrogenase 1; idh1 gene; idh2 gene; 5 hydroxymethylcytosine; isocitrate dehydrogenase 2; wt1 gene; human; article; dna hydroxymethylation; tet3 gene |
| Journal Title: | Cell Reports |
| Volume: | 9 |
| Issue: | 5 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2014-12-11 |
| Start Page: | 1841 |
| End Page: | 1856 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2014.11.004 |
| PROVIDER: | scopus |
| PMCID: | PMC4267494 |
| PUBMED: | 25482556 |
| DOI/URL: | |
| Notes: | Export Date: 2 January 2015 -- Source: Scopus |
