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

骨髓增生性肿瘤（MPN）是一类无药物治疗的血液疾病。在MPN患者中，转化为急性白血病构成了严重的并发症，严重限制了预期寿命。在过去的资助期间，我们描述了转录因子“核因子红细胞2”（NFE 2）在MPN患者中的活性升高，无论是通过wt-NFE 2的过表达还是通过突变的存在。我们已经表明，在各种小鼠模型中，增强的NFE 2活性导致MPN表型自发转化为白血病，这伴随着获得继发性基因组畸变和突变，也发现在MPN后白血病患者中。在这项研究中，我们将研究改变NFE 2活性促进获得额外的遗传变化的分子机制。我们推测，升高的NFE 2活性改变了NFE 2与相关因子“NFE 2样2”（NFE 2L 2）之间的DNA结合平衡，NFE 2样2识别类似的DNA元件。由于NFE 2L 2调节细胞保护基因的表达，我们认为增强的NFE 2活性通过增加ROS水平引起细胞内应激增加，从而导致DNA损伤，从而促进基因组不稳定性。

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.