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Two novel epigenetic pathways regulate NFE2 overexpression in myeloproliferative neoplasms

Jan C. Peeken, Jonas S. Jutzi, Julius Wehrle, Christoph Koellerer, Felix Staehle, Heiko Becker, Elias Schoenwandt, Thalia S. Seeger, Daniel H. Schanne, Monika Gothwal, Christopher J. Ott, Albert Gründer and Heike L. Pahl

Key points

  • Overexpression of NFE2 in Myeloproliferative Neoplasms is associated with H3Y41 Phosphorylation by JAK2V617F.

  • JMJD1C is a NFE2 Target Gene and Acts in a Positive Feedback Loop Contributing to NFE2 Overexpression in Myeloproliferative Neoplasms.

Abstract

The transcription factor "Nuclear Factor Erythroid 2" (NFE2) is overexpressed in the majority of patients with Myeloproliferative Neoplasms (MPN). In murine models, elevated NFE2 levels cause an MPN phenotype with spontaneous leukemic transformation. However, both the molecular mechanisms leading to NFE2 overexpression and its downstream targets remain incompletely understood. Here we show that the histone demethylase JMJD1C constitutes a novel NFE2 target gene. JMJD1C levels are significantly elevated in PV and PMF patients; concomitantly, global H3K9me1 and H3K9me2 levels are significantly decreased. JMJD1C binding to the NFE2 promoter is increased in PV patients, decreasing both H3K9me2 levels and binding of the repressive heterochromatin-protein-1α (HP1α). Hence, JMJD1C and NFE2 participate in a novel autoregulatory loop. Depleting JMJD1C expression significantly reduced cytokine independent growth of an MPN cell line. Independently, NFE2 is regulated through the epigenetic JAK2 pathway by phosphorylation of H3Y41. This likewise inhibits HP1α binding. Treatment with Decitabine lowered H3Y41ph and augmented H3K9me2 levels at the NFE2 locus in HEL cells, thereby increasing HP1α binding, which normalized NFE2 expression selectively in JAK2V617F positive cell lines.

  • Submitted October 18, 2017.
  • Accepted February 27, 2018.