Epigenetic regulation at the core Understanding the role of DOT1L in lymphocyte differentiation and cancer

This thesis describes the role of the epigenetic regulator DOT1L in lymphocyte development and cancer. DOT1L methylates lysine 79 on histone H3 (H3K79me), a mark that is generally associated with active transcription. A role for DOT1L has been described in several biological processes, including development and cellular reprogramming, and in cancers.
The current literature on the role of DOT1L in development and cancer is described in chapter one. Chapter two contains a literature review about the intriguing, but understudied subset of antigen-independent memory CD8⁺ T cells (T_AIM). DOT1L is an important epigenetic regulator of T_AIM differentiation.
In chapter three the effect of combined treatment of DOT1L inhibitors with HDAC inhibitors on cutaneous T cell lymphoma (CTCL) cell lines is studied. The identification of a mutation in DOT1L in a Dutch family with familiar melanoma is described in chapter four.
In the chapters five and seven, the role of DOT1L in T-cells and B-cells, respectively, is studied using mouse models with a cell-type specific deletion of Dot1L. DOT1L emerges as an important epigenetic regulator in both B-cell and T-cell development and differentiation. Based on these findings, the potential of using DOT1L modification to improve T-cell based anti-tumor therapy is investigated in chapter six.
Finally, the new insights about the role of DOT1L in lymphocyte differentiation and cancer obtained in this thesis are discussed in chapter eight.