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 myeloid cells. Most MPN patients have a point mutation in JAK2 ( JAK2 V617F ), which encodes a dominant-active kinase that constitutively triggers JAK/STAT signaling. In Drosophila, this pathway is simplified with a single JAK Hopscotch (Hop) and a single STAT transcription factor Stat92E. The hop Tumorous-lethal (Tum) allele encodes a dominant–active kinase that induces sustained Stat92E activation. Like MPN patients, hop Tum mutants have significantly more myeloid cells, which form invasive tumors. Through an unbiased genetic screen, we found that heterozygosity for Enhancer of Polycomb ( E(Pc) ), a component of the Tip60 lysine acetyltransferase complex, significantly increased tumor burden in hop Tum animals. Hematopoietic depletion of E(Pc) or other Tip60 components in an otherwise wild-type background also induced blood cell tumors. The E(Pc) tumor phenotype was dependent on JAK/STAT activity, as concomitant depletion of hop or Stat92E inhibited tumor formation. Stat92E target genes were significantly upregulated in E(Pc)- mutant myeloid cells, indicating that loss of E(Pc) activates JAK/STAT signaling. Neither the hop or Stat92E gene was upregulated upon hematopoietic E(Pc) depletion, suggesting that the regulation of the JAK/STAT pathway by E(Pc) is dependent on substrates other than histones. Indeed, E(Pc) 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 treatment for MPN patients.