Mechanisms of Notch signaling specificity in lymphocytes and their leukemic counterparts

Signaling pathways have evolved to ensure that external signals are sensed by a cell and translated into changes in gene expression that ultimately determine the differentiation and function of a cell. Mutations in components of signaling pathways uncouple these from the external signals they normally respond to, and thereby constitutively (in)activate these pathways, which can lead to disease, most notably cancer. In this thesis, we studied the role of one such pathway, Notch signaling, in the differentiation and function of lymphocytes and their leukemic counterparts. We identified a new role for Notch signaling in promoting cellular longevity of CD4+ T helper cells (chapter 5), and demonstrated that Notch uses direct and indirect mechanisms to promote differentiation of various T helper cell lineages (chapter 6). We also described a previously unappreciated role for Notch in driving the differentiation of human group 2 innate lymphoid cells (ILC2) (chapter 2) and present indications for the existence of ILC2 like leukemia, which also display mutational activation of the Notch pathway (chapter 3). Finally, we showed that - unlike in mice - human T cell development and sustained growth of T cell acute lymphoblastic leukemia cells do not depend on the ability of NOTCH1 to homodimerize (chapter 4). These findings further elucidate the diverse functions of Notch signaling in lymphocytes and its oncogenic potential in these cells, and therefore have important biomedical implications.