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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1841-1856
Number of pages16
JournalCell Reports
Volume9
Issue number5
DOIs
StatePublished - Jan 1 2014

Fingerprint

DNA Fingerprinting
Acute Myeloid Leukemia
Mutation
DNA
5-Methylcytosine
Methylation
Gene expression
5-hydroxymethylcytosine
Phenotype
Gene Expression

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Rampal, R., Alkalin, A., Madzo, J., Vasanthakumar, A., Pronier, E., Patel, J., ... Levine, R. L. (2014). DNA Hydroxymethylation Profiling Reveals that WT1 Mutations Result in Loss of TET2 Function in Acute Myeloid Leukemia. Cell Reports, 9(5), 1841-1856. https://doi.org/10.1016/j.celrep.2014.11.004

DNA Hydroxymethylation Profiling Reveals that WT1 Mutations Result in Loss of TET2 Function in Acute Myeloid Leukemia. / Rampal, Raajit; Alkalin, Altuna; Madzo, Jozef; Vasanthakumar, Aparna; Pronier, Elodie; Patel, Jay; Li, Yushan; Ahn, Jihae; Abdel-Wahab, Omar; Shih, Alan; Lu, Chao; Ward, Patrick S.; Tsai, Jennifer J.; Hricik, Todd; Tosello, Valeria; Tallman, Jacob E.; Zhao, Xinyang; Daniels, Danette; Dai, Qing; Ciminio, Luisa; Aifantis, Iannis; He, Chuan; Fuks, Francois; Tallman, Martin S.; Ferrando, Adolfo; Nimer, Stephen D; Paietta, Elisabeth; Thompson, Craig B.; Licht, Jonathan D.; Mason, Christopher E.; Godley, Lucy A.; Melnick, Ari; Figueroa, Maria; Levine, Ross L.

In: Cell Reports, Vol. 9, No. 5, 01.01.2014, p. 1841-1856.

Research output: Contribution to journalArticle

Rampal, R, Alkalin, A, Madzo, J, Vasanthakumar, A, Pronier, E, Patel, J, Li, Y, Ahn, J, Abdel-Wahab, O, Shih, A, Lu, C, Ward, PS, Tsai, JJ, Hricik, T, Tosello, V, Tallman, JE, Zhao, X, Daniels, D, Dai, Q, Ciminio, L, Aifantis, I, He, C, Fuks, F, Tallman, MS, Ferrando, A, Nimer, SD, Paietta, E, Thompson, CB, Licht, JD, Mason, CE, Godley, LA, Melnick, A, Figueroa, M & Levine, RL 2014, 'DNA Hydroxymethylation Profiling Reveals that WT1 Mutations Result in Loss of TET2 Function in Acute Myeloid Leukemia', Cell Reports, vol. 9, no. 5, pp. 1841-1856. https://doi.org/10.1016/j.celrep.2014.11.004
Rampal, Raajit ; Alkalin, Altuna ; Madzo, Jozef ; Vasanthakumar, Aparna ; Pronier, Elodie ; Patel, Jay ; Li, Yushan ; Ahn, Jihae ; Abdel-Wahab, Omar ; Shih, Alan ; Lu, Chao ; Ward, Patrick S. ; Tsai, Jennifer J. ; Hricik, Todd ; Tosello, Valeria ; Tallman, Jacob E. ; Zhao, Xinyang ; Daniels, Danette ; Dai, Qing ; Ciminio, Luisa ; Aifantis, Iannis ; He, Chuan ; Fuks, Francois ; Tallman, Martin S. ; Ferrando, Adolfo ; Nimer, Stephen D ; Paietta, Elisabeth ; Thompson, Craig B. ; Licht, Jonathan D. ; Mason, Christopher E. ; Godley, Lucy A. ; Melnick, Ari ; Figueroa, Maria ; Levine, Ross L. / DNA Hydroxymethylation Profiling Reveals that WT1 Mutations Result in Loss of TET2 Function in Acute Myeloid Leukemia. In: Cell Reports. 2014 ; Vol. 9, No. 5. pp. 1841-1856.
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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.",
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AU - Vasanthakumar, Aparna

AU - Pronier, Elodie

AU - Patel, Jay

AU - Li, Yushan

AU - Ahn, Jihae

AU - Abdel-Wahab, Omar

AU - Shih, Alan

AU - Lu, Chao

AU - Ward, Patrick S.

AU - Tsai, Jennifer J.

AU - Hricik, Todd

AU - Tosello, Valeria

AU - Tallman, Jacob E.

AU - Zhao, Xinyang

AU - Daniels, Danette

AU - Dai, Qing

AU - Ciminio, Luisa

AU - Aifantis, Iannis

AU - He, Chuan

AU - Fuks, Francois

AU - Tallman, Martin S.

AU - Ferrando, Adolfo

AU - Nimer, Stephen D

AU - Paietta, Elisabeth

AU - Thompson, Craig B.

AU - Licht, Jonathan D.

AU - Mason, Christopher E.

AU - Godley, Lucy A.

AU - Melnick, Ari

AU - Figueroa, Maria

AU - Levine, Ross L.

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