DNA Hydroxymethylation Profiling Reveals that WT1 Mutations Result in Loss of TET2 Function in Acute Myeloid Leukemia

Raajit K Rampal ,Todd Hricik,Omar Abdel-Wahab,Elodie Pronier,Qing Dai,Chuan He,Valeria Tosello,Aparna Vasanthakumar,Luisa Ciminio,Xinyang Zhao,Ari Melnick,Jihae Ahn,Altuna Alkalin,Elisabeth Paietta,Yushan Li,Iannis Aifantis,Danette L Daniels ,Patrick S Ward ,Christopher Mason ,Jacob E Tallman ,Jay P Patel ,Jennifer J Tsai ,Chao Lü ,François Fuks ,Adolfo A Ferrando ,Lucy A Godley ,María E Figueroa ,Martin S Tallman ,Stephen D Nimer ,Jozef Madžo ,Craig B Thompson ,Jonathan D Licht ,Alan H Shih ,Ross L Levine

doi:10.1016/j.celrep.2014.11.004

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.

Highlights

Gene discovery studies in human cancers have identified novel mutations that inform new mechanisms of malignant transformation
The observation that which impact TET2/TET3 but not TET1 (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 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

Summary

Introduction

Gene discovery studies in human cancers have identified novel mutations that inform new mechanisms of malignant transformation. One class of mutations found in AML and in other malignancies affects the conversion of 5-methylcytosine (5mC) to 5hydroxymethylcytosine (5hmC), mediated by the TET family of enzymes. These include mutations in TET2 and IDH1/IDH2. A similar effect is caused by aberrant production of the oncometabolite 2-hydroxyglutarate (2-HG) by gain-of-function IDH1/IDH2 mutations, which result in inhibition of TET enzyme catalytic functions (Figueroa et al, 2010a). These mutations define a class of AMLs with reduced genome-wide 5hmC. There are likely additional somatic mutations that can lead to direct or indirect alterations in TET enzyme function

Results

Discussion

Conclusion