EpiAML, v1
Research type
Research Study
Full title
Retroelement epigenomics of acute myeloid leukemia
IRAS ID
165893
Contact name
Miguel Branco
Sponsor organisation
Barts Health NHS Trust
Duration of Study in the UK
3 years, 0 months, 1 days
Research summary
Research Summary:
Gene activity is controlled by a number of different mechanisms, an important subset of which act at the level of DNA – these are called epigenetic mechanisms. Disruption of this carefully balanced control often leads to cancer. In acute myeloid leukemia (AML), mutations of genes involved in epigenetic mechanisms are commonly observed. However, we still have little understanding of the precise links between these mutations and cancer genesis/progression. In particular, studies have largely ignored the role of repetitive regions in the genome, which make up nearly half of the human genome and are common epigenetic targets that help to coordinate gene activity. In this study we aim to test whether mutations in two particular genes (DNMT3A and TET2) in AML affect epigenetic targeting of repetitive regions in the genome, which in turn could mediate broad changes in gene expression that are involved in cancer genesis and/or progression. We will use AML samples from a tissue bank and segregate them with respect to DNMT3A and TET2 mutations. We will then generate a number of genome-wide epigenetic profiles from these samples that will allow us to identify alterations at repetitive elements that are specifically linked with the aforementioned mutations. We will also measure gene activity, based on RNA abundance, to correlate the epigenetic changes with abnormal gene expression. Finally, we will directly test the role of DNMT3A and TET2 in mediating these epigenetic changes by performing genetic manipulation of AML samples.
Summary of results:
Over half of our genome composed of repeats of DNA sequences. Some of these repeats have the potential to move around within the genome and are called transposons. Transposons were initially dismissed as being “junk DNA”, without any function. Currently we know that transposons can control which genes are turned on or off and thus can modulate biological processes. Transposons are regulated by chemical modifications of DNA, called epigenetic modifications. If transposons are not correctly regulated, this can lead to abnormal gene activity and cause many different diseases, like cancer. Epigenetic changes are very common in acute myeloid leukaemia and this can activate transposons. Our aim was to understand how transposons contribute to the generation and survival of the cancer cells in AML.
We compared the epigenetic profiles of transposons in samples from poor-risk subtype AML and a favourable-risk subtype. We demonstrated that nine transposon families have the potential to alter gene expression in cancer cells from poor-risk AML. We also functionally tested the roles of two of these families using cultured AML cells. The inactivation of these elements leads to decreased cell growth, suggesting their activity contributed to cancer development.
REC name
Yorkshire & The Humber - Leeds East Research Ethics Committee
REC reference
14/YH/1312
Date of REC Opinion
17 Dec 2014
REC opinion
Favourable Opinion