Study Pro-Oncogenic Role of BCL6 in CLL Tumorigenesis

项目摘要 慢性淋巴细胞白血病是一种成人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，但这些药物可能会影响CLL的治疗。 不能治愈，并且会产生抗药性;通常会导致更具侵略性的疾病。鉴于此，理解 驱动CLL肿瘤发生和治疗抗性的分子事件值得深入研究。 CLL显示出显著的临床异质性，一些患者追求无痛病程，而另一些患者则 病情进展迅速，需要及早治疗。广泛的异质性也存在于遗传，表观遗传， 转录水平。除了组成性激活的BCR信号外，我们以前报道过存在一种 CLL细胞中的高活性受体酪氨酸激酶（RTK）AXL调节多种信号介质， 因此，PI 3 K/AKT和PLCγ2增强CLL细胞存活信号。 B细胞淋巴瘤6（BCL 6）是一种转录抑制因子和原癌基因，在先天性免疫缺陷中起着至关重要的作用。 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，我们已经检测到BCL 6在CLL细胞中的表达， CLL患者在mRNA和蛋白质水平。我们的初步研究结果表明，HSP 90的过度表达可能 调节CLL细胞中的BCL 6蛋白水平。重要的是，我们的初步数据还表明， BCL 6可能调节CLL细胞中高度活跃的AXL存活信号。然而，畸变的机制 CLL细胞中BCL 6的上调及其对CLL生物学和疾病的精确功能贡献 发病机制知之甚少。也不清楚异常的靶转录景观是否 在CLL细胞中表达的BCL 6与在正常生发中心B细胞中检测到的不同。因此 本申请的中心假设是BCL 6在CLL细胞中的过表达代表高度侵袭性 治疗时间较短的疾病。我们还假设BCL 6上调增强CLL细胞存活 信号和对BCR靶向药物的耐药性。目的1：评估CLL细胞中BCL 6是否上调 目的2：确定BCL 6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白血病细胞中的“高BCL 6”水平是否为慢性淋巴细胞白血病的风险因素 进展、治疗时间和治疗结果;确定BCL 6异常表达对CLL细胞的影响 存活率和对目前BCR靶向治疗的耐药性。因此，拟议的研究具有很大的潜力， 通过靶向CLL细胞中BCL 6建立新的预后参数和治疗途径 与目前的BCR靶向治疗，伊曲替尼。

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.