Dnmt3a is a critical tumour suppressor gene in the prevention of chronic lymphoid leukaemia (CLL) and CD8+ mature peripheral T cell lymphomas (PTCL), two B- and T- cell malignancies that have poor survival rates in humans.
The DNA methyltransferase Dnmt3a has an active and broad role in DNA methylation and gene regulation; using Dnmt3a knockout mice and molecular profiling, Haney, Upchurch et al. from University of Nebraska Medical Centre, USA has demonstrated that Dnmt3a is vital for safeguarding normal haematopoiesis.
Global deregulation of cytosine methylation is an epigenetic hallmark of hematologic malignancies that may promote tumorigenesis by silencing tumour suppressor genes, upregulating oncogenes, and inducing genomic instability. DNA methyltransferase 3a has emerged as a central regulator of haematopoiesis over the last few years, but the role of Dnmt3a in differentiation into hematopoietic lineages, and molecular functions on normal and malignant haematopoiesis remains poorly understood.
Haney, Upchurch et al. used Dnmt3aΔ/Δ mice to observe the phenotypic consequences of Dnmt3a inactivation. The majority of promoters are methylated and inactive in normal mouse CD8+ T cells; molecular profiling of methylation and gene expression identified promoter hypomethylation in Dnmt3aΔ/Δ minus mice as a major event in tumorigenesis of PTCL which is conserved across multiple Dnmt3aΔ/Δ and Dnmt3a+/- mouse lymphomas. Notably, the team identified downregulation of p53, suggesting p53 downregulation is a likely relevant in the initiation/progression of lymphomagenesis. Gene expression signatures from mouse PTCL were compared to those from human PTCL to demonstrate significant similarities between the two, suggesting similar molecular events may drive PTCL in both species.
The role of hypermethylation and silencing in disease development and progression in mice requires further investigation, and Haney, Upchurch et al. have produced a valuable model system to elucidate how epigenetic deregulation of transcription contributes to the pathogenesis of T cell lymphomas.
Dr Rene Opavsky, University of Nebraska Medical Centre, summarized the implications of these findings: "This work adds mature peripheral T cell lymphomas to a growing list of hematologic malignancies such as AML, MDS, CLL for which proper levels of Dnmt3a are critical to prevent their development in mice. It also highlights a potential role of genes hypomethylated in cancer in disease initiation and progression.”