Molecular Heterogeneity in Patients with Myeloproliferative Neoplasms - pathophysiological role of the transcription factor NFE2

骨髓增生性肿瘤(MPN)是一组血液系统疾病，目前尚无药物治疗方法。在MPN患者中，转化为急性白血病是一个严重的并发症，严重限制了预期寿命。在过去的资助期，我们描述了MPN患者中转录因子“核因子红系2”(NFE2)的活性升高，这可能是由于wt-NFE2的过度表达或由于突变的存在。我们已经证明，在不同的小鼠模型中，NFE2活性的增强会导致MPN表型自发转化为白血病，同时伴随着继发性基因组异常的获得，在MPN后白血病患者中也发现了突变。在这项资助中，我们将研究NFE2活性改变促进获得额外基因变化的分子机制。我们假设，NFE2活性的升高改变了NFE2与识别相似DNA元件的相关因子“NFE2-like-2”(NFE2L2)之间的DNA结合之间的平衡。由于NFE2L2调节细胞保护基因的表达，我们认为NFE2活性的增强通过增加ROS水平导致细胞内应激增加，从而导致DNA损伤，从而促进基因组的不稳定性。

Myeloproliferative Neoplasms (MPNs) constitute a group of hematological disorders for which no pharmacological cure exists. In MPN patients, transformation to acute leukemia constitutes a serious complication, that severely limits life expectancy. During the pasts funding periods, we described elevated activity of the transcription factor “nuclear factor erythroid 2” (NFE2) in MPN patients, either by overexpression of wt-NFE2 or by the presence of mutations. We have shown that in various murine models enhanced NFE2 activity causes an MPN phenotype with spontaneous transformation to leukemia, which is accompanied by the acquisition of secondary genomic aberrations and mutations also found in patients with post-MPN leukemias. In this grant we will investigate the molecular mechanism by which altered NFE2 activity promotes the acquisition of additional genetic changes. We hypothesize that elevated NFE2 activity shifts the balance between DNA binding of NFE2 and the related factor “NFE2-like-2” (NFE2L2), which recognizes similar DNA elements. As NFE2L2 regulates the expression of cytoprotective genes, we propose that enhanced NFE2 activity causes increased intracellular stress through augmented ROS levels, which lead to DNA damage, thereby promoting genomic instability.