Anderson Abigail M, Bailetti Alessandro A, Rodkin Elizabeth, De Atish, Bach Erika A
Department of Biochemistry and Molecular Pharmacology, The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, New York University School of Medicine, New York 10016.
Department of Biochemistry and Molecular Pharmacology, The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, New York University School of Medicine, New York 10016
G3 (Bethesda). 2017 Aug 7;7(8):2427-2438. doi: 10.1534/g3.117.044172.
A gain-of-function mutation in the tyrosine kinase JAK2 ( ) causes human myeloproliferative neoplasms (MPNs). These patients present with high numbers of myeloid lineage cells and have numerous complications. Since current MPN therapies are not curative, there is a need to find new regulators and targets of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling that may represent additional clinical interventions . offers a low complexity model to study MPNs as JAK/STAT signaling is simplified with only one JAK [Hopscotch (Hop)] and one STAT (Stat92E). is a gain-of-function mutation that causes dramatic expansion of myeloid cells, which then form lethal melanotic tumors. Through an F1 deficiency (Df) screen, we identified 11 suppressors and 35 enhancers of melanotic tumors in animals. Dfs that uncover the Hippo (Hpo) pathway genes () and () strongly enhanced the tumor burden, as did mutations in , , and other Hpo pathway genes. Target genes of the Hpo pathway effector Yorkie (Yki) were significantly upregulated in blood cells, indicating that Yki signaling was increased. Ectopic hematopoietic activation of Yki in otherwise wild-type animals increased hemocyte proliferation but did not induce melanotic tumors. However, hematopoietic depletion of Yki significantly reduced the tumor burden, demonstrating that Yki is required for melanotic tumors in this background. These results support a model in which elevated Yki signaling increases the number of hemocytes, which become melanotic tumors as a result of elevated JAK/STAT signaling.
酪氨酸激酶JAK2中的功能获得性突变导致人类骨髓增殖性肿瘤（MPN）。这些患者表现出大量髓系细胞且有许多并发症。由于目前的MPN疗法无法治愈，因此需要找到Janus激酶/信号转导子和转录激活子（JAK/STAT）信号通路的新调节因子和靶点，这可能代表额外的临床干预措施。果蝇提供了一个低复杂性模型来研究MPN，因为JAK/STAT信号通路仅通过一种JAK [跳房子（Hop）]和一种STAT（Stat92E）而被简化。Hop是一种功能获得性突变，可导致髓系细胞急剧扩增，进而形成致命的黑色素瘤。通过F1缺陷（Df）筛选，我们在果蝇动物中鉴定出11个黑色素瘤抑制因子和35个增强因子。揭示Hippo（Hpo）通路基因（疣（Wts））和（大肿瘤抑制因子1（Lats1））的Df强烈增强了Hop肿瘤负担，疣、大肿瘤抑制因子1和其他Hpo通路基因的突变也有同样的效果。Hpo通路效应器Yorkie（Yki）的靶基因在Hop血细胞中显著上调，表明Yki信号增强。在其他方面为野生型的动物中异位造血激活Yki可增加血细胞增殖，但不会诱发黑色素瘤。然而，Yki的造血耗竭显著降低了Hop肿瘤负担，表明在这种背景下Yki是黑色素瘤所必需的。这些结果支持了一个模型，即升高的Yki信号增加了血细胞数量，这些血细胞由于JAK/STAT信号升高而变成黑色素瘤。
