The Role of NOTCH1 in the Pathogenesis of CLL.

描述（由申请人提供）：慢性淋巴细胞白血病（CLL）是美国最常见的血液系统癌症。重要的是，与其他血液恶性肿瘤相比，CLL仅对化疗有一过性反应，并且没有可用的治愈性治疗。最近在10-15%的CLL病例中发现了NOTCH 1的激活突变，并且与不良预后、疾病进展、化疗抗性和向弥漫性大B细胞淋巴瘤（DLBCL）的转化相关（Fabbri et al.，J Exp Med 2011; Puente等人，Nature 2011）。值得注意的是，NOTCH 1信号传导可以用抑制性抗体和γ-分泌酶抑制剂有效阻断，目前正在开发作为用于治疗癌症的抗NOTCH疗法。我们的中心假设是，NOTCH 1突变可能有助于CLL的发病机制，通过破坏特定的转录程序，调节细胞增殖，分化和生存在CLL细胞。本研究计划的目标是确定NOTCH 1在CLL转化中的分子和细胞功能，分析突变型NOTCH 1在体内的致癌作用，并测试NOTCH抑制单独和与化疗联合治疗CLL的效果。

DESCRIPTION (provided by applicant: Chronic lymphocytic leukemia (CLL) is the most prevalent hematologic cancer in the US. Importantly, and in contrast with other hematologic malignancies, CLL responds only transiently to chemotherapy and there is no available curative therapy. Activating mutations in NOTCH1 have been recently found in 10-15% of CLL cases and are associated with poor prognosis, disease progression, chemotherapy resistance and transformation to diffuse large B cell lymphoma (DLBCL) (Fabbri et al., J Exp Med 2011; Puente et al, Nature 2011). Notably, NOTCH1 signaling can be effectively blocked with inhibitory antibodies and gamma-secretase inhibitors, currently under development as anti-NOTCH therapies for the treatment of cancer. Our central hypothesis is that NOTCH1 mutations may contribute to the pathogenesis of CLL by disrupting specific transcriptional programs that regulate cell proliferation, differentiation and survival in CLL cells. The goals of this research proposal are to define the molecular and cellular functions of NOTCH1 in CLL transformation, to analyze the oncogenic effects of mutant NOTCH1 in vivo, and to test the effects of NOTCH inhibition alone and in combination with chemotherapy in the treatment of CLL.