Cancer cells arise when normal cells lose control of proteins that regulate their growth and survival. Mutations in DNA may cause proteins to change or lose their normal functions and malfunctioning regulation systems may cause altered protein levels. Proteins interact with each other within cells to form networks that function to relay signals for growth and survival among many others. Although commonly we aim to target these mutated proteins in cancer, cooperating pathways may support cells in evading treatment from traditional therapies. In T-cell Acute Lymphoblastic Leukemia (T-ALL), Notch signaling is known to drive leukemia cell development and growth. Research also shows that pathways other than Notch signaling are needed to generate leukemia. Recent experiments suggest that RUNX proteins may assist Notch in making leukemias. However, mutations in RUNX1 have been recently described that are predicted to inhibit normal RUNX signals in this disease. The effects of these mutations have yet to be rigorously tested. We propose to manipulate the RUNX pathway to determine the contexts in which it is primarily supportive or detrimental to cancer growth. We will use a genetic approach to generate leukemias with different types of RUNX proteins: mutated and normal, to see if they generate leukemias faster, or delay and possibly prevent their onset. Additionally, we will attempt to generate leukemias in mice without any RUNX signaling to see if the pathway is absolutely necessary to make leukemia. Once we establish a role for RUNX mutations, we can begin further studies to see if we can better treat patients with T-ALL by targeting this pathway to reduce the likelihood that the disease will come back after treatment, and reduce the need for high-dose chemotherapy and its associated toxicities.