Mechanisms of differentiation blockade in CSF3R-mutant AML

项目总结 急性髓系白血病(AML)是一种致命的血癌，5年存活率仅为25%。其中一个驱动因素 尤其是集落刺激因子3受体(CSF3R)突变是AML预后较差的原因。正常的 CSF3R的功能是促进中性粒细胞前体细胞的扩张和向成熟细胞分化 中性粒细胞。在AML中，突变的CSF3R不能驱动分化。我们假设这种区别 逮捕对于CSF3R驱动的AML的侵略性生物学至关重要。 在急性髓细胞白血病中，分化停滞通常是由关键的造血转录因子的基因改变驱动的。 事实上，绝大多数CSF3R突变的AML患者在转录中都有共生突变 因子CEBPA，或核心结合因子(CBF)复合体的易位。这些基因改变破坏了 转录因子发挥作用，扰乱髓系细胞的表观遗传格局。我们的数据显示， 突变的CSF3R与突变的CEBPA或CBF易位相结合，产生了侵袭性较差的 分化型髓系白血病。此外，我们发现突变的CEBPA改变了信号的平衡 通过STAT蛋白在CSF3R下游，以牺牲PRO-2为代价，有利于增殖计划 差异化计划。最后，CBF易位抑制CEBPA的表达，提示CEBPA 突变或调控失调是CSF3R驱动的AML分化停滞的常见机制。 我们假设CEBPA突变和CBF易位通过改变STAT信号和 表观遗传功能障碍扰乱分化相关基因的转录。我们将对此进行测试 假设通过两个特定的目的：1)理解状态失调在CSF3R中的功能意义- 突变型AML，以及2)在CSF3R突变型AML中发现一种共同的分化阻断机制。 这些研究的成功完成将为我们提供对癌基因协同作用的机制的理解 在这个预后不良的CSF3R突变的AML亚组中。这将使Rational的未来发展成为可能 预防疾病复发的治疗方法。

PROJECT SUMMARY Acute Myeloid Leukemia (AML) is a lethal blood cancer, with a 5-year survival rate of only 25%. One driver of especially poor prognosis in AML is mutation of Colony Stimulating Factor 3 Receptor (CSF3R). The normal function of CSF3R is to promote the expansion of neutrophil precursors and their differentiation into mature neutrophils. In AML, mutant CSF3R is unable to drive differentiation. We hypothesize that this differentiation arrest is crucial to the aggressive biology of CSF3R-driven AML. In AML, differentiation arrest is often driven by genetic alterations in key hematopoietic transcription factors. Indeed, the vast majority of patients with CSF3R-mutant AML have co-occurring mutations in the transcription factor CEBPA, or translocations of the core binding factor (CBF) complex. These genetic alterations disrupt transcription factor function and perturb the epigenetic landscape of myeloid cells. Our data shows that the combination of mutant CSF3R with either mutant CEBPA or a CBF translocation produces an aggressive, poorly- differentiated myeloid leukemia. Furthermore, we find that mutant CEBPA alters the balance of signaling downstream of CSF3R through STAT proteins, to favor proliferative programs at the expense of pro- differentiation programs. Finally, CBF translocations suppress the expression of CEBPA, suggesting that CEBPA mutation or dysregulation is a common mechanism of differentiation arrest in CSF3R-driven AML. We hypothesize that CEBPA mutations and CBF translocations act through altered STAT signaling and epigenetic dysfunction to disrupt the transcription of differentiation-associated genes. We will test this hypothesis through two specific aims: 1) understand the functional significance of STAT dysregulation in CSF3R- mutant AML, and 2) identify a common mechanism of differentiation blockade in CSF3R-mutant AML. Successful completion of these studies will provide us with a mechanistic understanding of oncogene synergy in this poor prognosis CSF3R-mutant AML subgroup. This will enable the future development of rational therapeutic approaches to prevent disease relapse.