Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation Journal Article
| Authors: | Figueroa, M. E.; Abdel-Wahab, O.; Lu, C.; Ward, P. S.; Patel, J.; Shih, A.; Li, Y.; Bhagwat, N.; Vasanthakumar, A.; Fernandez, H. F.; Tallman, M. S.; Sun, Z.; Wolniak, K.; Peeters, J. K.; Liu, W.; Choe, S. E.; Fantin, V. R.; Paietta, E.; Löwenberg, B.; Licht, J. D.; Godley, L. A.; Delwel, R.; Valk, P. J. M.; Thompson, C. B.; Levine, R. L.; Melnick, A. |
| Article Title: | Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation |
| Abstract: | Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2-hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large acute myeloid leukemia (AML) patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of-function mutations were associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem/progenitor cell marker expression, suggesting a shared proleukemogenic effect. © 2010 Elsevier Inc. |
| Keywords: | adult; controlled study; unclassified drug; acute granulocytic leukemia; gene mutation; human cell; mutation; dna-binding proteins; leukemia, myeloid, acute; proto-oncogene proteins; phenotype; allele; cell function; gene expression profiling; cohort analysis; gene function; cell differentiation; dna methylation; transcription factors; oncogene; epigenetics; hematopoietic cell; binding site; catalysis; dna binding; loss of function mutation; cell mutant; isocitrate dehydrogenase; myeloid cells; gene regulatory networks; cell dna; 2 hydroxyglutaric acid; isocitrate dehydrogenase 1; isocitrate dehydrogenase isoenzyme; 5 methylcytosine; transcription factor gata; gene tet2; hydroxylation; 5-methylcytosine; gata1 transcription factor; proto-oncogenes |
| Journal Title: | Cancer Cell |
| Volume: | 18 |
| Issue: | 6 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2010-12-14 |
| Start Page: | 553 |
| End Page: | 567 |
| Language: | English |
| DOI: | 10.1016/j.ccr.2010.11.015 |
| PUBMED: | 21130701 |
| PROVIDER: | scopus |
| PMCID: | PMC4105845 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 5" - "Export Date: 20 April 2011" - "CODEN: CCAEC" - "Source: Scopus" |
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