DNAmethAML · Investigation of aberrant DNA methylation in malignant haematopoiesis
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-01-01 → 2019-12-31
- EU contribution
- €200,195
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Investigation of aberrant DNA methylation in malignant haematopoiesis
Acute myeloid leukaemia (AML) is a rapidly progressing haematopoietic malignancy, which is caused by diverse genetic aberrations. It is one of the most common myeloid malignancies with poor prognosis: the 5-year survival rate is only 19% for AML patients in Europe. The mutations in AML mainly occur in combinations and affect signaling molecules as well as important transcriptional and epigenetic regulators. High percentage of AML patients carries mutations in enzymes regulating DNA methylation and/or demethylation. Since DNA methylation is a reversible mark, it is a promising target for treatment of myeloid malignancies. However, to develop more efficient therapies there is a need to investigate potential functions of genome methylation and how its misregulation contributes to disease on mechanistic level. TET2 is one of the most-frequently mutated genes in AML (12-32%) and other haematopoietic disorders. It catalyses removal of DNA methylation mark. Several studies have shown that loss of TET2 function impedes the normal haematopoietic program and promotes self-renewal. Enhancers are specialized DNA regions that are bound by transcription factors that remotely target genes. Active enhancers do not usually have DNA methylation, suggesting that demethylation can be crucial for their function. However, the mechanism of how TET2 influences enhancers’ function is not known. Thus, the goal of my proposal is to investigate aberrant DNA methylation on enhancers in malignant haematopoiesis and to explore its functional role. To attain it, I have set the following objectives: 1) Identification and functional validation of methylation-sensitive enhancers; 2) Identification and characterization of methylation-sensitive transcription factors involved in stem cell self-renewal in leukaemogenesis.
Data: CORDIS, © European Union
Project objective
Acute myeloid leukaemia (AML) is an aggressive type of blood cancer characterized by uncontrollable growth of immature myeloid cells. Somatic mutations in diverse transcriptional regulators result in aberrant epigenetic landscape in leukemic cells, including patterns of DNA methylation. Due to its reversible nature, this epigenetic mark has been a promising therapeutic target and DNA methyltransferase inhibitors are already being used with varying degrees of success in clinic. The targeted improvement of existing therapies requires a better understanding of mechanisms how altered DNA methylation promotes malignancies. TET2, an enzyme catalysing DNA demethylation, is one of the most frequently mutated epigenetic regulators in AML. Its loss leads to hypermethylation at distal regulatory regions (or enhancers) and increased stem cell self-renewal and leukaemogenesis in the haematopoietic system. In the proposed work I plan to investigate the link between aberrant hypermethylation at enhancers and its role in developing and maintaining AML. Firstly, I will take advantage of clinically relevant AML mouse models that combine TET2 deficiency with AML-specific alterations and annotate DNA methylation-sensitive enhancers using high-throughput sequencing methods (MethylC-seq, ATAC-seq and ChIP-seq). Secondly, I will perform a positive-selection CRISPR-based high-throughput enhancer screen to identify DNA methylation-sensitive enhancers that inhibit leukemic stem cell self-renewal (i.e. tumour suppressive regulatory regions). Finally, I will identify and study the function of transcription factors which binding is lost due to aberrant DNA hypermethylation at these sites. The proposed work will be both discovery-based (genome-wide level) as well as mechanistic.
Original text from CORDIS.
Participants
- KOBENHAVNS UNIVERSITET · KOBENHAVNCoordinatorDenmark
Links
- View on CORDIS
- DOI: 10.3030/749362
- https://web.archive.org/web/20191123082435/https://www.bric.ku.dk/research/helin_group/
Data: CORDIS, © European Union