Dissecting the Role of HDAC1 in T Cell Lymphoma

Malignant diseases arise through both genetic alterations affecting DNA sequence but also through epigenetic modifications that result in altered chromatin structure and gene expression patterns. Among these modifications, reversible acetylation has been recognized as an important modification of N-terminal histone tails. The enzymes responsible for acetylation and deacetylation include histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Recent studies have provided insights into the mode of action of these enzymes and also into their function for normal development, cellular proliferation and cancer. Small molecule inhibitors targeting HDACs have been successfully used in the clinic and are currently under investigation for the treatment of diverse malignancies. Although inhibition of HDACs has commonly growth suppressive properties, deletion of a subset of HDACs in thymocytes resulted in transformation of T cells and lymphomagenesis. We aim to use a T cell lymphoma transgenic mouse model to study the function of the major histone deacetylses HDAC1 and HDAC2 for oncogene driven tumorigenesis. In this model, overexpression of a human oncogenic fusion-protein results in the formation of aggressive tumors. Interestingly, deletion of Hdac1 in T cells of these transgenic mice resulted in accelerated tumorigenesis and shortened survival of mice. It is our aim to study the role of HDAC1 and HDAC2 in this context and to compare the effects of genetic deletion of these enzymes to pharmacological inhibition using small molecule HDAC inhibitors. We want to perform molecular analyses to decipher the targets of HDAC1/2, including non-histone proteins that can be modified by reversible acetylation and thereby might impact on protein stability or function. Overall our study will provide novel molecular insights into the function of chromatin and protein acetylation for tumor development and will also investigate potential contraindications of HDAC inhibitors for treatment of selected patient groups or malignancies.

Malignant diseases arise through both genetic alterations affecting the DNA sequence (e.g mutations) but also through epigenetic modifications that affect the organization and regulation of our genome. Among these modifications, reversible acetylation has been recognized as an important modification of histone proteins, which are essential for the packaging of DNA into the cellular nucleus. Histone deacetylases (HDACs) remove acetyl moieties from histones and other proteins and thereby alter the compaction of the DNA into chromatin or the stability and function of proteins, respectively. Recent studies have provided insights into the mode of action of these enzymes and also into their function for normal development, cellular proliferation and cancer. Small molecule inhibitors targeting HDACs have been successfully used in the clinic and are currently under investigation for the treatment of diverse malignancies. Although inhibition of HDACs has commonly growth suppressive properties, deletion of a subset of HDACs in thymocytes resulted in transformation of a distinct subset of immune cells and lymphomagenesis. In this transnational project we aimed to study the function of the major histone deacetylases HDAC1 and HDAC2 for the development of a rare type of lymphoma, the so-called anaplastic large cell lymphoma (ALCL). We employed a mouse model, in which overexpression of a human oncogenic fusion-protein in T cells results in the formation of aggressive tumors. Deletion of Hdac1 and Hdac2 in T cells of these transgenic mice resulted in accelerated tumorigenesis and shortened survival of mice. Importantly, pharmacological inhibition of HDAC enzymes using small molecule inhibitors caused a significant delay in tumor development, or even a complete rescue if applied in higher doses. Different molecular analyses using genome-wide technologies showed that the deletion of HDACs caused specific alterations in histone and protein acetylation, especially targeting metabolic processes and DNA repair pathways. Further, the knockout of Hdac1 in the tumor model perturbed T cell specific gene expression patterns and induced a hyper-oncogenic molecular signature, which might be the reason for the accelerated tumor development. Overall the study results provide novel molecular insights into the function of chromatin and protein acetylation for tumor development and suggest that HDAC inhibitors might represent a novel therapeutic option for patients suffering from ALCL. It will be interesting in the future to further elucidate the differences in genetic T cell specific inhibition and the systemic effects of HDAC inhibitor treatment for tumorigenesis in this and other model systems.