Molecular pathways and targeted therapies in human leukemia

项目摘要 T系急性淋巴细胞白血病（T-ALL）是一种侵袭性血液癌症，其中 需要新的更有效的抗白血病药物来治疗患有 化疗耐药疾病。在这种情况下，鉴定激活突变的 在60%以上的T-ALL中存在NOTCH 1，这给靶向抗- NOTCH 1疗法在治疗这种疾病。然而，早期针对NOTCH 1的努力， 临床上受到有限的抗肿瘤活性的阻碍。我们已经证明 NOTCH 1是细胞生长和增殖的关键调节因子，并鉴定了MYC，PI 3 K-AKT 通路和白血病细胞代谢作为致癌程序的关键效应子 在NOTCH 1的下游。我们的中心假设是白血病的持续存在， 疾病的进展和复发是由信号传导、遗传、表观遗传和代谢回路驱动的， 绕过NOTCH 1信号传导的抗白血病作用。在这里，我们将：（一）解剖分子 将NOTCH 1与致癌转录程序连接的机制;（ii）功能分析 长程增强子在NOTCH 1诱导的转化中的作用;（iii）探索 肿瘤微环境信号，代谢和表观遗传可塑性作为肿瘤微环境的决定因素， 对抗NOTCH 1疗法的治疗反应和（iv）鉴定和功能表征 新的药物靶点和抗白血病药物与NOTCH抑制剂协同作用治疗 T-ALL。

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.