Remethylation of Dnmt3a−/− hematopoietic cells is associated with partial correction of gene dysregulation and reduced myeloid skewing

Shamika Ketkar, Angela M. Verdoni, Amanda M. Smith, Celia V. Bangert, Elizabeth R. Leight, David Y. Chen, Meryl K. Brune, Nichole M. Helton, Mieke Hoock, Daniel R. George, Catrina Fronick, Robert S. Fulton, Sai Mukund Ramakrishnan, Gue Su Chang, Allegra A. Petti, David H. Spencer, Christopher A. Miller, Timothy J. Ley

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Mutations in the DNA methyltransferase 3A (DNMT3A) gene are the most common cause of age-related clonal hematopoiesis (ARCH) in older individuals, and are among the most common initiating events for acute myeloid leukemia (AML). The most frequent DNMT3A mutation in AML patients (R882H) encodes a dominant-negative protein that reduces methyltransferase activity by ∼80% in cells with heterozygous mutations, causing a focal, canonical DNA hypomethylation phenotype; this phenotype is partially recapitulated in murine Dnmt3a/ bone marrow cells. To determine whether the hypomethylation phenotype of Dnmt3a/− hematopoietic cells is reversible, we developed an inducible transgene to restore expression of DNMT3A in transplanted bone marrow cells from Dnmt3a/ mice. Partial remethylation was detected within 1 wk, but near-complete remethylation required 6 mo. Remethylation was accurate, dynamic, and highly ordered, suggesting that differentially methylated regions have unique properties that may be relevant for their functions. Importantly, 22 wk of DNMT3A addback partially corrected dysregulated gene expression, and mitigated the expansion of myeloid cells. These data show that restoring DNMT3A expression can alter the epigenetic “state” created by loss of Dnmt3a activity; this genetic proof-of-concept experiment suggests that this approach could be relevant for patients with ARCH or AML caused by loss-of-function DNMT3A mutations.

Original languageEnglish
Pages (from-to)3123-3134
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number6
DOIs
StatePublished - Feb 11 2020

Keywords

  • DNA methylation
  • DNA methyltransferase
  • Gene expression
  • Hematopoiesis

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