Enhancer of Polycomb and the Tip60 complex repress hematological tumor initiation by negatively regulating JAK/STAT pathway activity.

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders that cause excessive production of myeloid cells. Most MPN patients have a point mutation in ( ), which encodes a dominant-active kinase that constitutively triggers JAK/STAT signaling. In , this pathway is simplified, with a single JAK, Hopscotch (Hop), and a single STAT transcription factor, Stat92E. The [ ] allele encodes a dominant-active kinase that induces sustained Stat92E activation. Like MPN patients, mutants have significantly more myeloid cells, which form invasive tumors. Through an unbiased genetic screen, we found that heterozygosity for [], a component of the Tip60 lysine acetyltransferase complex (also known as KAT5 in humans), significantly increased tumor burden in animals. Hematopoietic depletion of or other Tip60 components in an otherwise wild-type background also induced blood cell tumors. The tumor phenotype was dependent on JAK/STAT activity, as concomitant depletion of or inhibited tumor formation. Stat92E target genes were significantly upregulated in mutant myeloid cells, indicating that loss of activates JAK/STAT signaling. Neither the nor gene was upregulated upon hematopoietic depletion, suggesting that the regulation of the JAK/STAT pathway by E(Pc) is dependent on substrates other than histones. Indeed, depletion significantly increased expression of Hop protein in myeloid cells. This study indicates that E(Pc) works as a tumor suppressor by attenuating Hop protein expression and ultimately JAK/STAT signaling. Since loss-of-function mutations in the human homologs of E(Pc) and Tip60 are frequently observed in cancer, our work could lead to new treatments for MPN patients.This article has an associated First Person interview with the first author of the paper.