Study Pro-Oncogenic Role of BCL6 in CLL Tumorigenesis

项目总结 慢性淋巴细胞性白血病(CLL)是一种成人B细胞恶性肿瘤，约占白血病的三分之一 在美国的诊断。虽然B细胞受体(BCR)信号抑制剂正在改变CLL的管理，但这些 不能治愈，会产生抗药性；通常会导致更具侵袭性的疾病。有鉴于此，理解 驱动CLL肿瘤发生和治疗耐药的分子事件值得深入研究。 慢性淋巴细胞性白血病表现出显著的临床异质性，一些患者追求缓慢的病程，而另一些患者 进展迅速，需要及早治疗。广泛的异质性也存在于遗传、表观遗传和 转录水平。除了结构性活跃的bcr信号外，我们以前报告过存在 高活性受体酪氨酸激酶(RTK)Axl在CLL细胞中调节包括Lyn， 因此，PI3K/AKT和PLCγ2增强了CLL细胞的存活信号。 B细胞淋巴瘤6(BCL6)是一种转录抑制因子和原癌基因，在先天免疫缺陷中起重要作用。 以及适应性免疫系统和淋巴肿瘤，调节与DNA损伤有关的许多基因 和细胞增殖。最近，我们检测到BCL6在CLL细胞中的表达 慢性淋巴细胞性白血病患者在基因和蛋白水平均有表达。我们的初步发现表明，HSP90的过度表达可能 调节CLL细胞中BCL6蛋白水平。重要的是，我们的初步数据还表明， Bcl6可能参与调节CLL细胞内高活性的Axl生存信号。然而，异常的机制 BCL6在CLL细胞中的上调及其在CLL生物学和疾病中的精确功能贡献 其发病机制目前尚不清楚。目前也不清楚靶标转录景观是否异常 BCL6在CLL细胞中的表达与在正常生发中心B细胞中的表达不同。因此， 这一应用的中心假设是，在CLL细胞中过表达BCL6代表高度侵袭性 疾病的治疗时间更短。我们还假设BCL6上调增强了CLL细胞的存活 对bcr靶向药物的信号和耐药性。我们建议-目标1：评估BCL6在CLL细胞中是否上调 推动疾病进展；目标2：确定bcl6上调的机制及其在CLL细胞生物学中的作用 和信号。 拟议的深入研究将评估慢性淋巴细胞性白血病细胞中高水平的bcl6是否为慢性淋巴细胞性白血病的危险因素。 进展、治疗时间和治疗结果；确定bcl6异常表达对CLL细胞的影响 存活率和对当前bcr靶向治疗的抵抗力。因此，拟议的研究具有极大的潜力 联合靶向CLL细胞BCL6建立新的预后参数和治疗途径 在目前的bcr靶向治疗下，ibrutinib。

PROJECT SUMMARY Chronic lymphocytic leukemia (CLL) is an adult B-cell malignancy accounting for about a third of leukemia diagnoses in the US. While B-cell receptor (BCR)-signal-inhibitors are changing the management of CLL, these are not curative and resistance can develop; often leading to more aggressive disease. Given this, understanding the molecular events driving CLL oncogenesis and therapeutic resistance warrants in-depth investigation. CLL shows remarkable clinical heterogeneity, with some patients pursuing an indolent course, while others progress rapidly and require early treatment. Extensive heterogeneity exists also at the genetic, epigenetic, and transcriptional level. In addition to constitutively active BCR signal, we previously reported the existence of a highly active receptor tyrosine kinase (RTK) AXL in CLL cells regulating multiple signal mediators including LYN, PI3K/AKT and PLCγ2 thus, potentiating CLL cell survival signals. B-cell lymphoma 6 (BCL6) is a transcriptional repressor and proto-oncogene that plays a crucial role in the innate and adaptive immune system and lymphoid neoplasms, regulating numerous genes involved in DNA damage and cell proliferation. Most recently, we have detected expression of BCL6 in CLL cells from previously untreated CLL patients both at mRNA and protein levels. Our preliminary findings indicate that HSP90 overexpression may regulate BCL6 protein levels in CLL cells. Importantly, our initial data also suggest that aberrant expression of BCL6 may regulate the highly active AXL survival signal in CLL cells. However, the mechanism of aberrant upregulation of BCL6 in CLL cells, and its precise functional contributions to CLL biology and disease pathogenesis are poorly understood. It is also not clear if the target transcriptional landscape of aberrantly expressed BCL6 in CLL cells is different than that is detected in normal germinal center B-cells. Therefore, the central hypothesis of this application is that overexpression of BCL6 in CLL cells represents highly aggressive disease with shorter time to therapy. We also postulate that BCL6 upregulation potentiates CLL cell survival signals and resistance to BCR-targeted agents. We propose – Aim 1: Evaluate if BCL6 upregulation in CLL cells drives disease progression; Aim 2: Define the mechanism of BCL6 upregulation and its role in CLL cell biology and signaling. The proposed in-depth studies will assess if “high BCL6” level in CLL cells serves as a risk factor for CLL progression, time to therapy and treatment outcome; define the impact of BCL6 aberrant expression on CLL cell survival and resistance to current BCR-targeted therapies. Thus, the proposed studies have great potential to establish a new prognostic parameter and therapeutic avenue via targeting BCL6 in CLL cells in combination with the current BCR-targeted therapy, ibrutinib.