Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders that cause excessive production of 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} [hop ^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 (also known as KAT5 in humans), 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 nor 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 treatments for MPN patients.This article has an associated First Person interview with the first author of the paper.

中文翻译：

---

Polycomb和Tip60复合物的增强剂通过负调控JAK / STAT通路活性来抑制血液肿瘤的发生。

骨髓增生性肿瘤（MPN）是导致造血细胞过度生产的克隆性造血疾病。大多数MPN患者在JAK2（JAK2 ^V617F）中存在点突变，该突变编码组成性触发JAK / STAT信号的显性激活激酶。在果蝇中，使用单个JAK，Hopscotch（Hop）和单个STAT转录因子Stat92E简化了该途径。该跳^{肿瘤性致死}[跳^嵩]等位基因编码显性活性激酶诱导持续Stat92E活化。像MPN患者一样，跳^胃 突变体具有明显更多的骨髓细胞，形成侵袭性肿瘤。通过一个不带偏见的遗传屏幕中，我们发现，杂合梳的增强[ E（PC） ]时，Tip60的赖氨酸乙酰转移酶复合物（也被称为KAT5人类），显著提高了肿瘤负荷的一个组成部分跳^嵩动物。E（Pc）或其他Tip60成分在其他野生型背景下的造血耗竭也会引起血细胞肿瘤。该E（PC）的肿瘤表型依赖于JAK / STAT活性，如伴随耗尽一跳或Stat92E抑制肿瘤形成。Stat92E靶基因在上调显着E（Pc）-突变骨髓细胞，表明E（Pc）的丢失激活了JAK / STAT信号传导。既没有跳也不Stat92E基因在造血上调E（PC）耗尽，这表明JAK / STAT途径的由E（PC）的调节是依赖于组蛋白比其它底物。确实，E（Pc）耗竭显着增加了骨髓细胞中Hop蛋白的表达。这项研究表明，E（Pc）通过减弱Hop蛋白的表达并最终抑制JAK / STAT信号传导而起到抑癌作用。由于在癌症中经常观察到E（Pc）和Tip60的人类同源物功能丧失突变，因此我们的工作可能会为MPN患者带来新的治疗方法。本文对第一人进行了第一人称采访。