The Role of NOTCH1 in the Pathogenesis of CLL.

慢性淋巴细胞白血病（CLL）是美国最常见的血液学癌症。重要的是，与其他血液系统恶性肿瘤相比，CLL对化疗只有短暂的反应，并且没有有效的治疗方法。最近在10-15%的CLL病例中发现NOTCH1的激活突变，并与预后不良、疾病进展、化疗耐药和向弥漫性大B细胞淋巴瘤（DLBCL）的转化相关（Fabbri等，J Exp Med 2011； Puente等，Nature 2011）。值得注意的是，NOTCH1信号可以通过抑制性抗体和γ -分泌酶抑制剂有效阻断，目前正在开发用于治疗癌症的抗notch疗法。我们的中心假设是NOTCH1突变可能通过破坏CLL细胞中调节细胞增殖、分化和存活的特定转录程序而促进CLL的发病机制。本课题的研究目标是明确NOTCH1在CLL转化中的分子和细胞功能，分析突变NOTCH1在体内的致癌作用，检测单独抑制NOTCH和联合化疗治疗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.