Transcription factor nuclear factor erythroid-2 mediates expression of the cytokine interleukin 8, a known predictor of inferior outcome in patients with myeloproliferative neoplasms

Abstract

ARTICLES 1073 Myeloproliferative DisordersThe transcription factor nuclear factor erythroid-2 is over-expressed in patients with myeloproliferative neoplasms irrespective of the presence of the JAK2 V617F mutation. Our transgenic mouse model over-expressing nuclear factor erythroid-2, which recapitulates many features of myeloproliferative neoplasms including transformation to acute myeloid leukemia, clearly implicates this transcription factor in the pathophysiology of myeloproliferative neoplasms. Because the targets mediating nuclear factor erythroid-2 effects are not well characterized, we conducted microarray analysis of CD34 + cells lentivirally transduced to over-express nuclear factor erythroid-2 or to silence this transcription factor via shRNA, in order to identify novel target genes. Here, we report that the cytokine interleukin 8 is a novel target gene. Nuclear factor erythroid-2 directly binds the interleukin 8 promoter in vivo, and these binding sites are required for promoter activity. Serum levels of interleukin 8 are known to be elevated in both polycythemia vera and primary myelofibrosis patients. Recently, increased interleukin 8 levels have been shown to be predictive of inferior survival in primary myelofibrosis patients in multivariate analysis. Therefore, one of the mechanisms by which nuclear factor erythroid-2 contributes to myeloproliferative neoplasm pathology may be increased interleukin 8 expression.Transcription factor nuclear factor erythroid-2 mediates expression of the cytokine interleukin 8, a known predictor of inferior outcome in patients with myeloproliferative neoplasms

Smoking is associated with increased risk of myeloproliferative neoplasms: A general population‐based cohort study

“…Smoking is also associated with increased hypoxia‐inducible factor signaling and interleukin 1‐beta secretion from mononuclear cells, leading to upregulation of nuclear factor erythoid‐2 expression in megakaryocytic cells and IL‐8 secretion . These observations are indeed intriguing, as both are believed to play a vigorous role in MPN‐pathogenesis as well …”

Myeloproliferative neoplasms: from origins to outcomes

“…[92][93][94] Furthermore, elevated levels of NFE-2 (itself induced by inflammatory cytokine IL-1b) drive MPN proliferation and progression through modulation of inflammatory cascades, including elevated IL-8 expression. 95,96 Overall, it remains unclear exactly how a single phenotypic driver mutation initiates a clonal expansion that will evolve into an overt MPN, but current evidence suggests that the constitutional genetic background, aging process, and tumor microenvironment are key factors, with each exerting cell-intrinsic and environmental effects (Figure 3).…”

Epigenetic regulation of NFE2 overexpression in myeloproliferative neoplasms

“…In a first series of experiments, we modulated NFE2 levels in purified human CD34 1 hematopoietic stem cells (HSCs). 6 NFE2 levels were increased in HSCs by lentiviral overexpression of the complementary DNA or decreased by expression of a short hairpin RNA (shRNA). These data identified the proinflammatory cytokine interleukin 8 (IL8) as a novel NFE2 target.…”

“…These data identified the proinflammatory cytokine interleukin 8 (IL8) as a novel NFE2 target. 6 As IL8 levels constitute an independent prognostic factor for survival in primary myelofibrosis (PMF) patients, 7 these data underline the role of altered NFE2 activity in the pathophysiology of MPNs.…”