NF‐E2 overexpression delays erythroid maturation and increases erythrocyte production

Abstract

The transcription factor Nuclear Factor-Erythroid 2 (NF-E2) is overexpressed in the vast majority of patients with polycythaemia vera (PV). In murine models, NF-E2 overexpression increases proliferation and promotes cellular viability in the absence of erythropoietin (EPO). EPO-independent growth is a hallmark of PV. We therefore hypothesized that NF-E2 overexpression contributes to erythrocytosis, the pathognomonic feature of PV. Consequently, we investigated the effect of NF-E2 overexpression in healthy CD34+ cells. NF-E2 overexpression led to a delay in erythroid maturation, manifested by a belated appearance of glycophorin A-positive erythroid precursors. Maturation delay was similarly observed in primary PV patient erythroid cultures compared to healthy controls. Protracted maturation led to a significant increase in the accumulated number of erythroid cells both in PV cultures and in CD34 + cells overexpressing NF-E2.Similarly, NF-E2 overexpression altered erythroid colony formation, leading to an increase in erythroid burst-forming unit formation. These data indicate that NF-E2 overexpression delays the early phase of erythroid maturation, resulting in an expansion of erythroid progenitors, thereby increasing the number of erythrocytes derived from one CD34 + cell. These data propose a role for NF-E2 in mediating the erythrocytosis of PV.

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

“…Delayed erythroid maturation has previously been observed by elevating NF-E2 levels in human CD34 + hematopoietic stem cells. 32 Our current data thus corroborates the importance of correct NF-E2 levels for physiological erythroid maturation. Delayed maturation can result from inefficient or absent elimination of internal organelles from maturing reticulocytes.…”

Lentiviral gene ontology (LeGO) vectors equipped with novel drug-selectable fluorescent proteins: new building blocks for cell marking and multi-gene analysis

“…3 Indeed, recently LeGO vectors have successfully been used in both murine and human HSC for short hairpin RNAmediated transcriptional silencing. 4,16 In this study, we have shown that LeGO vectors facilitate efficient gene expression in (human) MSCs, which represent a highly relevant target. 12,17 In addition, the novel LeGO vectors containing the CAG promoter 14 have widened the field of potential applications.…”

AML1 is overexpressed in patients with myeloproliferative neoplasms and mediates JAK2V617F-independent overexpression of NF-E2

“…We have recently shown that NF-E2 overexpression delays the early phase of erythroid maturation, resulting in an expansion of erythroid progenitors, thereby increasing the number of erythrocytes derived from one CD34 ϩ cell. 10 These data propose a role for NF-E2 in mediating the dysregulated erythrocytosis of PV.…”