Myc-induced pathways in B cell lymphoma initiation and survival

 描述（由申请方提供）：Myc癌基因在至少70%的人类恶性肿瘤中过度表达或失调，包括B细胞淋巴瘤。Myc是一种转录因子，其驱动细胞周期进程并诱导导致肿瘤的细胞转化。 发展尽管近年来在阐明抑制或促进Myc诱导的肿瘤发展的基因方面取得了重大进展，但对Myc在肿瘤发展的任何阶段激活的信号通路知之甚少。此外，参与癌症“成瘾”或依赖Myc继续生存和生长的信号通路仍然没有得到解决。我们已经开始调查这些关于Myc的公开问题。我们最近已经确定Myc激活未转化的B细胞中的Ras信号传导途径，其抑制Myc诱导的细胞凋亡并且在B细胞淋巴瘤发生期间显著促进Myc的转化活性。然而，目前尚不清楚其他信号通路是否被Myc活性改变，这些活性有助于Myc的转化能力，以及Ras信号通路或其他通路是否是过表达Myc的癌症的癌基因成瘾的因素。此外，并非群体中的所有细胞都可以以相同的方式对Myc激活做出反应，从而导致群体对Myc的反应异质性。因此，我们假设在正常B细胞中，Myc在转化的初始阶段诱导了多种信号传导途径，其中一些有助于淋巴瘤的发展，另一些则导致细胞死亡。我们还假设Myc依赖性B细胞淋巴瘤的生长和存活需要特定的信号通路。为了解决这些假设，我们提出了两个具体目标。目的1将集中在未转化的B细胞中Myc改变的信号通路。目的2将集中在B细胞淋巴瘤中介导Myc成瘾的途径。技术的最新进展现在允许分析群体中单个细胞中的信号传导，以及每个细胞基础上的数十个个体信号传导事件。信号事件的单细胞分析将确定由Myc激活的途径以及每个Aim中对Myc的反应范围。这些研究的完成将显著地推进对Myc诱导的B细胞转化中的起始信号事件和有助于Myc癌基因成瘾的途径的理解。我们的研究也可能导致在B细胞淋巴瘤的新的治疗靶向途径的阐明。

 DESCRIPTION (provided by applicant): The Myc oncogene is overexpressed or dysregulated in at least 70% of all human malignancies, including B cell lymphomas. Myc is a transcription factor that drives cell cycle progression and induces cellular transformation that results in tumor development. Although significant advances have been made in recent years elucidating the genes that inhibit or contribute to Myc-induced tumor development, very little is known about the signaling pathways that are activated by Myc at any stage of tumor development. Moreover, the signaling pathways that are involved in cancers that become "addicted" or rely on Myc to continue to survive and grow remain unresolved. We have begun investigations into these open questions about Myc. We have recently determined that Myc activates the Ras signaling pathway in untransformed B cells, which inhibits Myc- induced apoptosis and significantly contributes to the transforming activity of Myc during B cell lymphomagenesis. However, it is unclear whether other signaling pathways are altered by Myc activity that contribute to the transformation ability of Myc, and if the Ras signaling pathway or other pathways are a factor in the oncogene addiction of the cancers that overexpress Myc. In addition, not all of the cells in a population may respond in the same way to Myc activation, resulting in population heterogeneity in response to Myc. Therefore, we hypothesize that in normal B cells, multiple signaling pathways are induced by Myc in the initial stages of transformation, and some of these contribute to lymphoma development and others to cell death. We also hypothesize that specific signaling pathways are required for Myc-addicted B cell lymphomas to grow and survive. To address these hypotheses we propose two Specific Aims. Aim 1 will focus on the signaling pathways altered by Myc in untransformed B cells. Aim 2 will focus on the pathways that mediate Myc addiction in B cell lymphomas. Recent advances in technology now allow analysis of signaling in single cells in a population, and dozens of individual signaling events on a per cel basis. Single cell analysis of signaling events will determine the pathways that are activated by Myc and the range of reactions to Myc in each Aim. Completion of these studies will significantly advance understanding into the initiating signaling events in Myc- induced B cell transformation and the pathways that contribute to Myc oncogene addiction. Our studies are also likely to result in the elucidation of novel therapeutically targetable pathways in B cell lymphoma.