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

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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.