Title: Aberrant DNA methylation and its impact in blood cancer development
Funder: Cancer Research UK

Abstract: Background Despite advances in diagnosis and supportive care of patients suffering from blood cancers many patients still succumb to their disease. Patients are generally treated with various cytotoxic agents, and aggressive cases with additional stem cell transplantation, to achieve complete and durable remission. However, despite the establishment of these treatment modalities, lack of response to treatment, high rates of relapse, and comorbidities incompatible with curative chemotherapy, continue to make blood cancers, especially in the elderly, a major problem for the patients and the healthcare system. This indicates a strong need for better and more targeted treatment options. Recent findings suggest that disruption of the epigenome can give rise to cancer and drive tumor progression. The methylcytosine dioxygenase TET2 as well as the DNA methyltransferase DNMT3A are both involved in the regulation of DNA methylation patterns, play central roles in hematopoietic stem cell homeostasis, and are frequently mutated in blood cancers. Aims The overarching goal of this project is to uncover fundamental biological aspects of DNA methylation and chromatin in gene expression and use this knowledge to explore novel therapeutic opportunities for treatment of blood cancers with mutations in the DNA methylation machinery. I will combine the expertise from my past and current work to, i) uncover how TET2 is recruited to specific genomic regions, ii) systematically investigate the impact of aberrant cytosine modifications at enhancers in a native chromatin context, and iii) explore mouse models of blood cancer to identify biomarkers and novel treatment options of clinical significance. Methods Fundamental aspects of DNA methylation will be addressed using mouse embryonic stem cells and human and mouse blood cancer cells lines. Here, I will employ CRISPR/Cas9-based genome editing to generate well-defined genetic systems and combine them with state-of-the-art biochemical analysis, proteomics and genomics. The in vivo relevance of findings will be confirmed by conditional mouse mutagenesis and validated in genetically modified mouse models of human Acute Myeloid Leukemia as well as patient-derived xenograft models. How the results of this research will be used I expect to generate important and novel insights into basic epigenetic mechanisms in hematopoiesis. This provides the basis to understand the clonal evolution of blood cancer and has the potential to reveal vulnerabilities in malignant hematopoietic cells that carry mutations in TET2 and DNMT3A. Successful identification of biomarkers, drug targets and active anti-cancer compounds will be developed further in collaboration with partners in academia and the pharmaceutical industry.

Lay abstract: Background Despite advances in diagnosis and supportive care of patients suffering from blood cancers many patients still succumb to their disease. Patients are generally treated with various cytotoxic agents, and aggressive cases with additional stem cell transplantation, to achieve complete and durable remission. However, despite the establishment of these treatment modalities, lack of response to treatment, high rates of relapse, and comorbidities incompatible with curative chemotherapy, continue to make blood cancers, especially in the elderly, a major problem for the patients and the healthcare system. This indicates a strong need for better and more targeted treatment options. Recent findings suggest that disruption of the epigenome can give rise to cancer and drive tumor progression. The methylcytosine dioxygenase TET2 as well as the DNA methyltransferase DNMT3A are both involved in the regulation of DNA methylation patterns, play central roles in hematopoietic stem cell homeostasis, and are frequently mutated in blood cancers. Aims The overarching goal of this project is to uncover fundamental biological aspects of DNA methylation and chromatin in gene expression and use this knowledge to explore novel therapeutic opportunities for treatment of blood cancers with mutations in the DNA methylation machinery. I will combine the expertise from my past and current work to, i) uncover how TET2 is recruited to specific genomic regions, ii) systematically investigate the impact of aberrant cytosine modifications at enhancers in a native chromatin context, and iii) explore mouse models of blood cancer to identify biomarkers and novel treatment options of clinical significance. Methods Fundamental aspects of DNA methylation will be addressed using mouse embryonic stem cells and human and mouse blood cancer cells lines. Here, I will employ CRISPR/Cas9-based genome editing to generate well-defined genetic systems and combine them with state-of-the-art biochemical analysis, proteomics and genomics. The in vivo relevance of findings will be confirmed by conditional mouse mutagenesis and validated in genetically modified mouse models of human Acute Myeloid Leukemia as well as patient-derived xenograft models. How the results of this research will be used I expect to generate important and novel insights into basic epigenetic mechanisms in hematopoiesis. This provides the basis to understand the clonal evolution of blood cancer and has the potential to reveal vulnerabilities in malignant hematopoietic cells that carry mutations in TET2 and DNMT3A. Successful identification of biomarkers, drug targets and active anti-cancer compounds will be developed further in collaboration with partners in academia and the pharmaceutical industry.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS