Personalized therapy for AML patients with a newly identified genetic alteration

项目概述：在过去的几十年里，新疗法的开发进展甚微 急性髓系白血病患者的选择。这在很大程度上是因为我们对多少循环基因的了解有限 变化确实会影响疾病的进展。因此，非常需要识别新的基因改变。 这推动了急性髓细胞白血病，建立了对这些变化如何影响疾病进展的机械理解， 并为有这些变化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的表达是 携带9q21.32缺失的AML患者减少，这种单倍体不足直接抑制其 P21和C/eBPα的转录激活(在PRESS，癌细胞)。与减少表达相反，我们 我还发现HNRNPK在30%以上没有HNRNPK的AML患者中扩增和过度表达 缺失，导致较差的临床反应和结果。此外，多变量分析显示， HnRNP K过表达驱动c-Myc的表达，也与最常见的 AML(突变型NPM1)，以加剧白血病的发生。鉴于我们目前对hnRNP如何 K过度表达影响AML进展，此应用程序将询问hnRNP K癌基因功能和 确定其与突变型NPM1在急性髓系白血病中的协同关系。从机制上讲，hnRNP K也被认为是 通过其转录和翻译功能，激活c-Myc等癌基因的表达。因此， 探讨hnRNP K在调节急性髓系白血病c-Myc表达中的作用对于了解其如何 HnRNP K的过度表达推动了疾病的进展，因为这可能代表了一种未描述的机制 在AML中没有MYC扩增或易位的情况下驱动c-Myc的表达。 我们的假设是hnRNP K是一个未鉴定的癌基因，它刺激c-Myc表达和 与突变体NPM1合作，推动白血病的发生。这项建议的目标是了解 HnRNP K介导的驱动白血病发生的机制，决定了hnRNP K和 突变的NPM1，并确定利用这些变化的治疗方法。使用基因定义的 初级患者样本和新的转基因动物模型，我们将对1)进行评估。如何使用hnRNP K 过度表达影响白血病的发生和髓系分化，2)。HnRNP K如何直接调节c- 3)MYC通路及治疗反应。HnRNP K过度表达如何与突变型NPM1协同作用 推动白血病进展4)。HnRNP K直接调节独特转录的机制 以及管理白血病发生的翻译程序。 这些研究将从根本上促进我们对hnRNP K癌基因功能和 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。

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.