Mechanisms of differentiation blockade in CSF3R-mutant AML

项目摘要 急性髓细胞白血病（AML）是一种致命的血液癌症，5年生存率仅为25%。的一个驱动因素 AML中预后特别差的是集落刺激因子3受体（CSF 3R）突变。正常 CSF 3R的功能是促进中性粒细胞前体细胞的扩增及其向成熟细胞的分化。 中性粒细胞在AML中，突变的CSF 3R不能驱动分化。我们假设这种差异 在CSF 3R驱动的AML的侵袭性生物学中，抑制是至关重要的。 在AML中，分化停滞通常由关键造血转录因子的遗传改变驱动。 事实上，绝大多数CSF 3R突变型AML患者在转录中存在共发突变， 因子CEBPA，或核心结合因子（CBF）复合物的易位。这些基因改变破坏了 转录因子的功能，并扰乱骨髓细胞的表观遗传景观。我们的数据显示， 突变型CSF 3R与突变型CEBPA或CBF易位的组合产生了一种侵袭性的、不良的- 分化型髓系白血病此外，我们发现突变的CEBPA改变了信号传导的平衡， 下游的CSF 3R通过STAT蛋白，有利于增殖程序的代价是亲， 差异化方案。最后，CBF易位抑制CEBPA的表达，这表明CEBPA可能是一种新的基因。 突变或失调是CSF 3R驱动的AML中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信号传导起作用， 表观遗传功能障碍，以破坏分化相关基因的转录。我们将测试这个 通过两个具体的目标：1）理解STAT失调在CSF 3R中的功能意义， 突变型AML，和2）鉴定CSF 3R-突变型AML中分化阻断的共同机制。 这些研究的成功完成将为我们提供一个癌基因协同作用机制的理解 CSF 3R突变型AML亚组的预后差。这将使未来的发展理性化 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.