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The Unfolded Protein Response Is a Major Driver of LCN2 Expression in BCR-ABL- and JAK2V617F-Positive MPN. | LitMetric

AI Article Synopsis

  • Lipocalin 2 (LCN2) is a proinflammatory mediator linked to the development of myeloproliferative neoplasms (MPN), showing a significant upregulation in LCN2 mRNA levels in patients with chronic myeloid leukemia and myelofibrosis compared to healthy individuals.
  • Elevated serum levels of LCN2 were found in polycythemia vera and myelofibrosis, correlating with specific genetic mutations and neutrophil counts.
  • The study identifies the endoplasmic reticulum stress response as a key factor driving LCN2 expression, suggesting that targeting this pathway could offer new therapeutic options for MPN treatment.

Article Abstract

Lipocalin 2 (LCN2), a proinflammatory mediator, is involved in the pathogenesis of myeloproliferative neoplasms (MPN). Here, we investigated the molecular mechanisms of LCN2 overexpression in MPN. LCN2 mRNA expression was 20-fold upregulated in peripheral blood (PB) mononuclear cells of chronic myeloid leukemia (CML) and myelofibrosis (MF) patients vs. healthy controls. In addition, LCN2 serum levels were significantly increased in polycythemia vera (PV) and MF and positively correlated with JAK2V617F and mutated CALR allele burden and neutrophil counts. Mechanistically, we identified endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) as a main driver of LCN2 expression in BCR-ABL- and JAK2V617F-positive 32D cells. The UPR inducer thapsigargin increased LCN2 expression >100-fold, and this was not affected by kinase inhibition of BCR-ABL or JAK2V617F. Interestingly, inhibition of the UPR regulators inositol-requiring enzyme 1 (IRE1) and c-Jun -terminal kinase (JNK) significantly reduced thapsigargin-induced LCN2 RNA and protein expression, and luciferase promoter assays identified nuclear factor kappa B (NF-κB) and CCAAT binding protein (C/EBP) as critical regulators of mLCN2 transcription. In conclusion, the IRE1-JNK-NF-κB-C/EBP axis is a major driver of LCN2 expression in MPN, and targeting UPR and LCN2 may represent a promising novel therapeutic approach in MPN.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391615PMC
http://dx.doi.org/10.3390/cancers13164210DOI Listing

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