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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 in DNA 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.

SUBMITTER: Rampal R 

PROVIDER: S-EPMC4267494 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia.

Rampal Raajit R   Alkalin Altuna A   Madzo Jozef J   Vasanthakumar Aparna A   Pronier Elodie E   Patel Jay J   Li Yushan Y   Ahn Jihae J   Abdel-Wahab Omar O   Shih Alan A   Lu Chao C   Ward Patrick S PS   Tsai Jennifer J JJ   Hricik Todd T   Tosello Valeria V   Tallman Jacob E JE   Zhao Xinyang X   Daniels Danette D   Dai Qing Q   Ciminio Luisa L   Aifantis Iannis I   He Chuan C   Fuks Francois F   Tallman Martin S MS   Ferrando Adolfo A   Nimer Stephen S   Paietta Elisabeth E   Thompson Craig B CB   Licht Jonathan D JD   Mason Christopher E CE   Godley Lucy A LA   Melnick Ari A   Figueroa Maria E ME   Levine Ross L RL  

Cell reports 20141204 5


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  ...[more]

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