• What is DNMT3A?
  • DNMT3A in Myelodysplastic Syndromes
  • DNMT3A Mutations
  • Clinical Trials

DNMT3A

The DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A) gene encodes a protein involved in epigenetic gene regulation (Gene 2013; Li et al. 2007).

DNMT3A is most frequently mutated in hematologic malignancies such as acute myeloid leukemia and myelodysplastic syndromes, but it has also been observed in other cancers, including lung cancer (Kim et al. 2013).

Related Pathways

Contributors: Scott Wheeler, Ph.D. (through June 2014), Adam Seegmiller, M.D., Ph.D., Cindy L. Vnencak-Jones, Ph.D.

Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones. 2015. DNMT3A. My Cancer Genome https://www.padiracinnovation.org/content/disease/myelodysplastic-syndromes/dnmt3a/?tab=0 (Updated December 4).

Last Updated: December 4, 2015

DNMT3A in Myelodysplastic Syndromes

DNMT3A mutations occur in 7.8% of MDS (COSMIC). DNMT3A mutations are observed in all types of MDS (Cazzola, Della Porta, and Malcovati 2013). DNMT3A mutations most often occur at the R882 residue of the protein in MDS (COSMIC), and they are believed to cause loss of function (Shih et al. 2012). However, other mutations are spread throughout the gene. DNMT3A mutations affect DNA methylation and, as such, play a role in cancer development through deregulation of gene expression.

DNMT3A mutations have been associated with poor outcomes in some (RCMD and RAEB) but not all types of MDS (Cazzola, Della Porta, and Malcovati 2013; Walter et al. 2011). In addition, Bejar et al. (2014) observed that DNMT3A mutations predict shorter overall survival following hematopoietic stem cell transplantation. In RARS, DNMT3A mutations often co-occur with SF3B1 mutations, and no association between DNMT3A mutations and poor outcome is observed (Bejar et al. 2012; Cazzola, Della Porta, and Malcovati 2013).​

Contributors: Stephen A. Strickland, M.D., MSCI, Annette S. Kim, M.D., Ph.D.

Suggested Citation: Strickland, S., A. Kim. 2014. DNMT3A in Myelodysplastic Syndromes. My Cancer Genome https://www.padiracinnovation.org/content/disease/myelodysplastic-syndromes/dnmt3a/ (Updated September 23).

Last Updated: September 23, 2014

DNMT3A Mutations in Myelodysplastic Syndromes

Properties
Location of mutations DNMT3A gene on 2p23
Frequency of DNMT3A mutations in MDS 7.8% (COSMIC)
Implications for Targeted Therapeutics
Response to bromodomain inhibitors, DOT1L inhibitors, or other targeted epigenetic therapies Unknown at this timea
Response to spliceosome-targeting therapies Unknown at this timeb
Response to Ras-targeting therapies Unknown at this timec

DNMT3A mutations have been associated with poor outcomes in some (RCMD and RAEB) but not all types of MDS (Cazzola, Della Porta, and Malcovati 2013; Walter et al. 2011). In addition, Bejar et al. (2014) observed that DNMT3A mutations predict shorter overall survival following hematopoietic stem cell transplantation. In RARS, DNMT3A mutations often co-occur with SF3B1 mutations, and no association between DNMT3A mutations and poor outcome is observed (Bejar et al. 2012; Cazzola, Della Porta, and Malcovati 2013).

a Bromodomain (BRD2, BRD3, BRD4, and BRDt) inhibitors and DOT1L inhibitors are in phase I studies in hematologic malignancies (Abdel-Wahab and Levine 2013). In addition, several other epigenetic targeted therapies, targeting IDH1/IDH2, EZH2, LSD1, or UTX/JMJD3, are in development (Abdel-Wahab and Levine 2013).

b Drugs targeting the spliceosome are in development; these drugs alter gene expression or affect alternative splicing in ways that inhibit cancer progression (Bonnal, Vigevani, and Valcarcel 2012).

c Efforts to develop Ras-targeting therapies are in progress and are hoped to be useful in hematologic malignancies (Ward, Braun, and Shannon 2012).

Contributors: Stephen A. Strickland, M.D., MSCI, Annette S. Kim, M.D., Ph.D.

Suggested Citation: Strickland, S., A. Kim. 2014. DNMT3A Mutations in Myelodysplastic Syndromes. My Cancer Genome https://www.padiracinnovation.org/content/disease/myelodysplastic-syndromes/dnmt3a/322/ (Updated September 23).

Last Updated: September 23, 2014

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