Molecular pathways and targeted therapies in human leukemia

项目总结

PROJECT SUMMARY 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 60% of T-ALL has brought great interest to the development of targeted anti- NOTCH1 therapies in the treatment of this disease. However, early efforts to target NOTCH1 in the clinic have been hampered by limited antitumor activity. We have demonstrated that NOTCH1 is a critical regulator of cell growth and proliferation and identified MYC, the PI3K-AKT pathway and leukemia cell metabolism as critical effectors of the oncogenic program downstream of NOTCH1. Our central hypothesis is that leukemia persistence, disease progression and relapse are driven by signaling, genetic, epigenetic and metabolic circuits that bypass the antileukemic effects of NOTCH1 signaling. Here we will: (i) dissect molecular mechanisms wiring NOTCH1 with oncogenic transcriptional programs; (ii) functionally analyze the role of long-range enhancers in NOTCH1-induced transformation; (iii) explore the role of tumor microenvironment signals, metabolic and epigenetic plasticity as determinants of the therapeutic response to anti-NOTCH1 therapies and (iv) identify and functionally characterize new drug targets and antileukemic drugs synergistic with NOTCH inhibition for the treatment of T-ALL.