NFE2 codes for a subunit of the NF-E2 (nuclear factor, erythroid 2) complex essential for regulating erythroid and megakaryocytic maturation and differentiation. This submit regulates a number of erythroid and megakaryocytic promoters. Rare insertion and deletion mutations leading to premature translation termination in NFE2 were found in 2% of myeloproliferative neoplasms (MPN). NFE2 mutatoins appear to be enriched in isolated myeloid sarcomas (MS). Of the six investigated cases of MS without previous or concurrent AML in the bone marrow, 4 (67%) harbored mutations in NFE2, 3 of which were missense and 1 of which was frameshift. In addition, NFE2 is overexpressed in the majority of patients with MPNs. In murine models, over-expression of NFE2 caused an MPN phenotype with spontaneous leukemic transformation, supporting a direct role of NFE2 in the pathogenesis of MPN. Over-expression of NFE2 in MPN may be attributed to histone H3Y41 phosphorylation by V617F-mutated JAK2 and transcriptional activation of NFE2 by JMJD1C in a positive feedback loop.
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