T cell acute lymphoblastic leukemia (T-ALL) is an aggressive form of leukemia derived from malignant early T cell blood progenitors. It accounts for 10–15% of pediatric and 20–25% of adult cases of the total number of acute lymphoblastic leukemia (ALL) in Europe, the United States and Japan. It is the most common malignancy diagnosed in children, representing nearly one third of all pediatric cancers with a peak incidence in children aged 2-5 years. The current treatment is severely toxic. Moreover, despite intensive chemotherapy, 20% of pediatric and over 50% of adult T-ALL patients fail to achieve a complete remission which, inexorably results in fatal outcomes. These devastating effects highlight the need to determine the molecules involved in the onset and spread of T-ALL, which may lead to the development of novel targeted therapies.
PHF6 is a tumor suppressor gene commonly mutated by deactivation in adult and pediatric T-ALL. This gene plays an important role in hematopoietic stem cell (HSC) self-renewal, the process by which these blood progenitors generate new blood cells for the lifetime of an organism. PHF6 inactivation enhances HSC self-renewal in mice and drives enhanced T-ALL leukemia stem cell activity. However, the mechanisms by which loss of PHF6 contributes to leukemia remain poorly understood. By testing genetic data and analyzing the interactions of PHF6 at the protein level, I have identified a second mutated gene in T-ALL called PHIP. Notably, loss of PHF6 and PHIP show convergent cellular and developmental phenotypes supporting a common molecular and functional role. My central hypothesis is that PHF6 and PHIP mutations contribute to leukemia through common mechanisms. Specifically, here I will biochemically characterize the protein composition of the PHF6 and PHIP complex to evaluate the mechanisms by which they control gene expression. Moreover, I will assess the proposed convergent role of PHIP and PHF6 in the control of normal HSC-self renewal as well as the oncogenic transformation of healthy cells to T-ALL cells. These results will improve our understanding of the leukemia initiating potential of HSCs potentially providing new therapeutic targets to prevent T-ALL initiation and progression. Ultimately, these studies will likely contribute to patient stratification and personalized treatment based on their specific molecular profiles.
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