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

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...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2013-04, Vol.110 (15), p.6091-6096
Main Authors: Tang, Jian Zhong, Carmichael, Catherine L., Shi, Wei, Metcalf, Donald, Ng, Ashley P., Hyland, Craig D., Jenkins, Nancy A., Copeland, Neal G., Howell, Viive M., Zhao, Zhizhuang Joe, Smyth, Gordon K., Kile, Benjamin T., Alexander, Warren S.
Format: Article
Language:English
Subjects:
Alleles
Animals
Biological Sciences
DNA Transposable Elements
Erythrocytes
Erythroid cells
Gene expression
Gene Expression Regulation, Leukemic
Gene loci
Genes
Genetic loci
Genetic transposition
Genotype
Janus Kinase 2 - genetics
Janus Kinase 2 - metabolism
Leukemia
Leukemia, Erythroblastic, Acute - genetics
Leukemia, Erythroblastic, Acute - metabolism
Leukemia, Megakaryoblastic, Acute - genetics
Leukemia, Megakaryoblastic, Acute - metabolism
Liver cells
Mice
Mice, Transgenic
Mutagenesis
Neoplasm Transplantation
Oncogene Proteins - genetics
Oncogene Proteins - metabolism
Promoter Regions, Genetic
Proto-Oncogene Protein c-ets-1 - genetics
Proto-Oncogene Protein c-ets-1 - metabolism
Proto-Oncogene Proteins c-ets - genetics
Proto-Oncogene Proteins c-ets - metabolism
Recombination, Genetic
Rodents
Sequence Analysis, DNA
Signal transduction
Signal Transduction - genetics
Spleen cells
Stem cells
Transcription Factors
Transcriptional Regulator ERG
Transposons
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1304234110