New mutations and epigenetic modifications in MPNs. Several genes mutated in MPN (black boxes) are implicated either in histone modifications or in DNA methylation control. (A) JAK2 activation phosphorylates histone H3Y41, leading to the exclusion of heterochromatin protein 1α (HP1α) from chromatin. In addition, mutant JAK2 phosphorylates PRMT5, thus impairing the methylation of histone H4 and H2A arginine residues. Both phosphorylations are expected to facilitate gene transcription or reduce gene repression. (B) EZH2 belongs to the PRC2 complex, which methylates H3K27 and may also recruit DNMTs. ASXL1 may belong to a complex (PR-DUB in Drosophila melanogaster) that deubiquitinates histone H2AK119, a function that antagonizes the effect of the PRC1 complex. Inactivation of both genes is expected to prevent transcriptional repression mediated by the PRC complexes. (C) TET2 converts DNA 5mC to 5hmC, thus playing a role in active DNA demethylation that would be associated with gene expression. Activation mutations of JAK2 and mutations impairing EZH2, ASXL1, and TET2 functions may result in the deregulation of both DNA methylation and chromatin structure, resulting in aberrant gene expression, gene activation, or failure of repression.