A novel role for nuclear factor-erythroid 2 in erythroid maturation by modulation of mitochondrial autophagy.

We have recently demonstrated that the transcription factor NF-E2, which is critical for erythroid maturation and globin gene expression, plays an important role in the pathophysiology of myeloproliferative neoplasms. Myeloproliferative neoplasm patients display elevated levels of NF-E2 and transgenic mice overexpressing the transcription factor develop myeloproliferative neoplasm, albeit, surprisingly without erythrocytosis. NF-E2 transgenic mice show both a reticulocytosis and a concomitant increase in iron deposits in the spleen, suggesting both enhanced erythrocyte production and increased red blood cell destruction. We therefore hypothesized that elevated NF-E2 levels may lead to increased erythrocyte destruction by interfering with organelle clearance during erythroid maturation. We have previously shown that NF-E2 overexpression delays erythroid maturation of human hematopoietic stem cells. Here we report that increased NF-E2 levels also impede murine maturation by retarding mitochondrial depolarization and delaying mitochondrial elimination. In addition, ribosome autophagy is delayed in transgenic s. We demonstrate that the autophagy genes Nix and Ulk1 are direct novel NF-E2 target genes, as these loci are bound by NF-E2 in chromatin immunoprecipitation assays. Moreover, Nix and Ulk1 expression is increased in transgenic mice and in granulocytes from polycythemia vera patients. This is the first report implying a role for NF-E2 in erythroid maturation by affecting autophagy.