The role of NOTCH1 in T-cell acute lymphoblastic leukemia.
T-lineage acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer in which novel more effective antileukemic drugs are needed for the treatment of patients with chemotherapy resistant disease. In this context the identification of activating mutations of NOTCH1 in over 50% of T-ALL has brought great interest to the development of targeted anti-NOTCH1 therapies. However, early efforts to develop effective anti NOTCH therapies have been hampered by our limited understanding of the target genes and oncogenic pathways controlled by NOTCH1 in T-ALL. Our central hypothesis is that the aberrant activation of NOTCH1 signaling controls a complex transcriptional regulatory network responsible for the transformation of T-cell progenitor cells. Moreover, we propose that improved understanding of the oncogenic mechanisms downstream of NOTCH1 will result in improved anti-NOTCH1 targeted therapies in T-ALL. Our preliminary results show that NOTCH controls leukemia gene expression in concert with other regulatory factors; has long range effects in gene regulation and identify Hes1 as a critical mediator of NOTCH induced transformation. Thus, the goals of this project are: (i) to analyze the role of NOTCH1 in the combinatorial control of gene expression during T-cell transformation; (ii) to identify the role of NOTCH1 in the activity of long-range gene regulation; and (iii) to analyze the genes and pathways controlled by HES1 and to establish their contribution to the pathogenesis of NOTCH-induced T-ALL.
This ALSF Bridge Grant has funded research on the role of NOTCH1, a critical gene mutated in pediatric T-cell leukemias with the immediate goal of securing the renewal of a federal grant supporting this research . Towards this goal we have analyzed in detail the activity and function of NOTCH1 in leukemia cells and generated new highly innovative results including the identification of new drugs that can kill leukemia cells in combination with NOTCH inhibitors. Moreover we have successfully secured the renewal of our federal grant which was recently ranked in the top 4.9% at the NIH.