Grant: Travel Awards - Institute Community Support

T-cell Acute Lymphoblastic Leukemia (T-ALL) represents a subtype of blood cancer which affects children at relatively high frequency in addition to cases seen in adults. While high dose chemotherapy can achieve cure in children, relapsed patients and adults have poor outcomes and cure comes at the cost of a lifetime of side effects. Recent data from our group suggests that two proteins, RUNX1 and NOTCH1, may work together to enhance global networks of signalling. These results suggest that RUNX1 may function to support leukemia growth but must be reconciled with recent next-generation sequencing data which has identified recurrent mutations in the RUNX1 gene. We reduced the amount of RUNX1 is T-leukemic cells and found it to impair their growth by a number of assays and induced an arrest in the the cells ability to replicate and divide. We next depleted cells of RUNX1 and NOTCH1 and attempted to understand how this might regulate the epigenetics of the cells which refers to the changes to the genome that are not accompanied by a change in DNA sequence but rather to the proteins around which DNA is bound. In addition to this, we have identified several proteins which RUNX1 regulates through its actions in gene regulation that may explain its actions in supporting growth: IL7R, IGF1R, MYC, and CDKN1B (p27). These results suggest that RUNX1 may support Notch signaling by interactions with the epigenome, resulting in net growth support. Potential therapies which seek to reduce the amount of RUNX1 signaling should be investigated for efficacy against T-ALL cells with the end goal of reducing the amount of chemotherapy used and achieving higher rates of cure.