title: Transposon mutagenesis reveals cooperation of ETS family transcription factors with signaling pathways in erythro-megakaryocytic leukemia.
abstract: To define genetic lesions driving leukemia, we targeted cre-dependent Sleeping Beauty (SB) transposon mutagenesis to the blood-forming system using a hematopoietic-selective vav 1 oncogene (vav1) promoter. Leukemias of diverse lineages ensued, most commonly lymphoid leukemia and erythroleukemia. The inclusion of a transgenic allele of Janus kinase 2 (JAK2)V617F resulted in acceleration of transposon-driven disease and strong selection for erythroleukemic pathology with transformation of bipotential erythro-megakaryocytic cells. The genes encoding the E-twenty-six (ETS) transcription factors Ets related gene (Erg) and Ets1 were the most common sites for transposon insertion in SB-induced JAK2V617F-positive erythroleukemias, present in 87.5% and 65%, respectively, of independent leukemias examined. The role of activated Erg was validated by reproducing erythroleukemic pathology in mice transplanted with fetal liver cells expressing translocated in liposarcoma (TLS)-ERG, an activated form of ERG found in human leukemia. Via application of SB mutagenesis to TLS-ERG-induced erythroid transformation, we identified multiple loci as likely collaborators with activation of Erg. Jak2 was identified as a common transposon insertion site in TLS-ERG-induced disease, strongly validating the cooperation between JAK2V617F and transposon insertion at the Erg locus in the JAK2V617F-positive leukemias. Moreover, loci expressing other regulators of signal transduction pathways were conspicuous among the common transposon insertion sites in TLS-ERG-driven leukemia, suggesting that a key mechanism in erythroleukemia may be the collaboration of lesions disturbing erythroid maturation, most notably in genes of the ETS family, with mutations that reduce dependence on exogenous signals.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
authors.forename: Jian Zhong
authors.initials: JZ
authors.lastname: Tang
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Carmichael
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Ashley P
authors.initials: AP
authors.lastname: Ng
authors.forename: Craig D
authors.initials: CD
authors.lastname: Hyland
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Viive M
authors.initials: VM
authors.lastname: Howell
authors.forename: Zhizhuang Joe
authors.initials: ZJ
authors.lastname: Zhao
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
mesh_terms: D000483:Alleles; D000818:Animals; D004251:DNA Transposable Elements; D015973:Gene Expression Regulation, Leukemic; D005838:Genotype; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics / Q000378:metabolism*; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D009368:Neoplasm Transplantation; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG
chemical_list: D004251:DNA Transposable Elements; C531115:ERG protein, mouse; C494042:Ets1 protein, mouse; D015513:Oncogene Proteins; D050784:Proto-Oncogene Protein c-ets-1; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2