Personalized therapy for AML patients with a newly identified genetic alteration

项目概述：过去几十年来，新治疗方法的开发进展甚微 AML患者的选择。这在很大程度上是由于我们对有多少复发性遗传病的了解有限。 改变确实影响疾病进展。因此，非常需要鉴定新的遗传改变 驱动AML，建立这些变化如何影响疾病进展的机制理解， 并为这些改变的患者开发治疗方法。 为此，我们最近发现，DNA和RNA结合蛋白hnRNP K的表达， 在携带9q21.32缺失的AML患者中减少，这种单倍不足直接抑制了其 p21和C/EBP α的转录激活（出版中，Cancer Cell）。与减少表达相反，我们 还发现HNRNPK在超过30%的AML患者中扩增和过表达，而没有这种表达。 缺失，导致不良的临床反应和结果。此外，多变量分析显示， hnRNP K过表达驱动c-Myc表达，并且还与最常见的基因突变协同作用。 AML（突变型NPM1）加重白血病发生。鉴于我们目前对hnRNP如何 K过表达影响AML进展，该应用将询问hnRNP K致癌功能， 确定其与AML中突变型NPM 1的协同关系。从机制上讲，hnRNP K也被认为是 通过其转录和转录功能激活癌基因如c-Myc的表达。因此，在本发明中， 探索hnRNPK在AML中介导c-Myc表达的作用对于理解hnRNPK如何介导c-Myc表达是至关重要的。 hnRNP K过表达驱动疾病进展，因为这可能代表一种未表征的机制， 在AML中不存在MYC扩增或易位的情况下驱动c-Myc表达。 我们假设hnRNP K是一种刺激c-Myc表达的非特征性癌基因， 与突变的NPM1协同作用来驱动白血病的发生。本提案的目的是了解 hnRNP K介导的驱动白血病发生的机制，决定了hnRNP K和 突变NPM1，并确定利用这些改变的治疗方法。使用基因定义的 主要患者样品和新的转基因动物模型，我们将评估1）。如何hnRNP K 过表达影响白血病发生和髓样分化，2）。hnRNP K如何直接调节c- Myc通路和治疗反应，3）。hnRNP K过表达如何与突变型NPM 1协同作用， 驱动白血病进展4）。hnRNP K直接调节独特转录的机制 和控制白血病发生的翻译程序。 这些研究将从根本上推进我们对hnRNP K致癌功能的理解， 确定hnRNP K是否可用于对患者进行风险分层，并作为靶向治疗的标志物。

Project Summary: The past several decades have seen little progress in the development of new treatment options for AML patients. This is due in large part to our limited understanding of how many recurrent genetic alterations truly impact disease progression. Thus, there is a great need to identify novel genetic alterations that drive AML, establish a mechanistic understanding of how these changes influence disease progression, and develop therapeutic approaches for patients with these alterations. To this end, we recently identified that expression of the DNA and RNA binding protein hnRNP K is reduced in AML patients harboring a 9q21.32 deletion and this haploinsufficiency directly inhibits its transcriptional activation of p21 and C/EBPα (In press, Cancer Cell). In contrast to reduced expression, we also discovered that HNRNPK is amplified and overexpressed in over 30% of AML patients without this deletion, resulting in poor clinical responses and outcomes. Furthermore, multivariate analyses revealed that hnRNP K overexpression drives c-Myc expression and also cooperates with the most common alteration in AML (mutant NPM1) to exacerbate leukemogenesis. Given our current lack of understanding as to how hnRNP K overexpression impacts AML progression, this application will interrogate hnRNP K oncogenic functions and determine its cooperative relationship with mutant NPM1 in AML. Mechanistically, hnRNP K is also thought to activate expression of oncogenes like c-Myc, through its transcriptionally and translationally functions. Thus, exploring the role of hnRNP K in mediating c-Myc expression in AML is critical for understanding as to how hnRNP K overexpression drives disease progression, as this may represent an uncharacterized mechanism to drive c-Myc expression in the absence of MYC amplifications or translocations in AML. It is our hypothesis that hnRNP K is an uncharacterized oncogene that stimulates c-Myc expression and cooperates with mutant NPM1 to drive leukemogenesis. The objectives of this proposal are to understand the hnRNP K-mediated mechanisms that drive leukemogenesis, determine the synergism between hnRNP K and mutant NPM1, and identify therapeutic approaches to exploit these alterations. Using genetically defined primary patient samples and novel transgenic animal models, we will evaluate 1). how hnRNP K overexpression impacts leukemogenesis and myeloid differentiation, 2). how hnRNP K directly regulates the c- Myc pathway and therapeutic responses, 3). how hnRNP K overexpression synergizes with mutant NPM1 in driving leukemic progression 4). the mechanisms by which hnRNP K directly regulates unique transcriptional and translational programs governing leukemogenesis. These studies will fundamentally advance our understanding of hnRNP K oncogenic functions and determine whether hnRNP K can be used to risk stratify patients and serve as a marker for targeted therapy.