title: Cooperative epigenetic modulation by cancer amplicon genes.
abstract: Chromosome band 9p24 is frequently amplified in primary mediastinal B cell lymphoma (PMBL) and Hodgkin lymphoma (HL). To identify oncogenes in this amplicon, we screened an RNA interference library targeting amplicon genes and thereby identified JAK2 and the histone demethylase JMJD2C as essential genes in these lymphomas. Inhibition of JAK2 and JMJD2C cooperated in killing these lymphomas by decreasing tyrosine 41 phosphorylation and increasing lysine 9 trimethylation of histone H3, promoting heterochromatin formation. MYC, a major target of JAK2-mediated histone phosphorylation, was silenced after JAK2 and JMJD2C inhibition, with a corresponding increase in repressive chromatin. Hence, JAK2 and JMJD2C cooperatively remodel the PMBL and HL epigenome, offering a mechanistic rationale for the development of JAK2 and JMJD2C inhibitors in these diseases.
authors.affiliation: Metabolism Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Rui
authors.forename: N C Tolga
authors.initials: NC
authors.lastname: Emre
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kruhlak
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Chung
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.forename: Graham
authors.initials: G
authors.lastname: Slack
authors.forename: George W
authors.initials: GW
authors.lastname: Wright
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.forename: Vu N
authors.initials: VN
authors.lastname: Ngo
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Shaffer
authors.forename: Weihong
authors.initials: W
authors.lastname: Xu
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Yandan
authors.initials: Y
authors.lastname: Yang
authors.forename: Laurence
authors.initials: L
authors.lastname: Lamy
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.forename: Wenming
authors.initials: W
authors.lastname: Xiao
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.forename: David
authors.initials: D
authors.lastname: Maloney
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Hans Konrad
authors.initials: HK
authors.lastname: Muller-Hermelink
authors.forename: Kerry
authors.initials: K
authors.lastname: Savage
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Rimsza
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.forename: Erlend B
authors.initials: EB
authors.lastname: Smeland
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Weisenburger
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: David
authors.initials: D
authors.lastname: Levens
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D045744:Cell Line, Tumor; D002899:Chromosomes, Human, Pair 9; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology; D008479:Mediastinal Neoplasms / Q000235:genetics*; D010766:Phosphorylation
chemical_list: D006657:Histones; C413655:KDM4C protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; C507924:JAK2 protein, human; D053614:Janus Kinase 2