Transposon mutagenesis reveals cooperation of ETS family transcription factors with signaling pathways in erythro-megakaryocytic leukemia

Tang, JZ; Carmichael, CL; Shi, W; Metcalf, D; Ng, AP; Hyland, CD; Jenkins, NA; Copeland, NG; Howell, VM; Zhao, ZJ; Smyth, GK; Kile, BT; Alexander, WS

Author(s): Tang, JZ; Carmichael, CL; Shi, W; Metcalf, D; Ng, AP; Hyland, CD; Jenkins, NA; Copeland, NG; Howell, VM; Zhao, ZJ; Smyth, GK; Kile, BT; Alexander, WS;
Details: Publication Year 2013-04-09,Volume 110,Issue #15,Page 6091-6096
Journal Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Publication Type: Journal Article
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.
Publisher: NATL ACAD SCIENCES
Keywords: ACUTE MYELOID-LEUKEMIA; HEMATOPOIETIC STEM-CELLS; FACTOR ERG; PROGENITOR CELLS; DIFFERENTIATION; MICE; PROTOONCOGENE; MUTATIONS; OVEREXPRESSION; EXPRESSION
Research Division(s): Cancer And Haematology; Bioinformatics
Link To PubMed Central Version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625293/
Publisher's Version: https://doi.org/10.1073/pnas.1304234110

Creation Date: 2013-04-09 12:00:00