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dc.contributor.authorvan, der Weyden Louiseen
dc.contributor.authorGiotopoulos, Georgeen
dc.contributor.authorWong, Kimen
dc.contributor.authorRust, Alistair Gen
dc.contributor.authorRobles-Espinoza, Carla Den
dc.contributor.authorOsaki, Hikarien
dc.contributor.authorHuntly, Brianen
dc.contributor.authorAdams, David Jen
dc.date.accessioned2016-09-29T15:07:12Z
dc.date.available2016-09-29T15:07:12Z
dc.date.issued2015-08-13en
dc.identifier.citationBMC Cancer. 2015 Aug 13;15(1):585
dc.identifier.issn1471-2407
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/260536
dc.description.abstractAbstract Background B-cell precursor acute lymphoblastic leukemia (B-ALL) is amongst the leading causes of childhood cancer-related mortality. Its most common chromosomal aberration is the ETV6-RUNX1 fusion gene, with ~25 % of ETV6-RUNX1 patients also carrying PAX5 alterations. Methods We have recreated this mutation background by inter-crossing Etv6-RUNX1 (Etv6 RUNX1-SB ) and Pax5 +/− mice and performed an in vivo analysis to find driver genes using Sleeping Beauty transposon-mediated mutagenesis and also exome sequencing. Results Combination of Etv6-RUNX1 and Pax5 +/− alleles generated a transplantable B220 + CD19+ B-ALL with a significant disease incidence. RNA-seq analysis showed a gene expression pattern consistent with arrest at the pre-B stage. Analysis of the transposon common insertion sites identified genes involved in B-cell development (Zfp423) and the JAK/STAT signaling pathway (Jak1, Stat5 and Il2rb), while exome sequencing revealed somatic hotspot mutations in Jak1 and Jak3 at residues analogous to those mutated in human leukemias, and also mutation of Trp53. Conclusions Powerful synergies exists in our model suggesting STAT pathway activation and mutation of Trp53 are potent drivers of B-ALL in the context of Etv6-RUNX1;Pax5 +/− .
dc.titleSomatic drivers of B-ALL in a model of ETV6-RUNX1; Pax5 +/− leukemiaen
dc.typeArticle
dc.date.updated2016-09-29T15:07:12Z
dc.language.rfc3066en
dc.rights.holdervan der Weyden et al.
prism.publicationDate2015en
dc.identifier.doi10.17863/CAM.4770
dcterms.dateAccepted2015-07-27en
rioxxterms.versionofrecord10.1186/s12885-015-1586-1en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-08-13en
dc.contributor.orcidGiotopoulos, George [0000-0003-1390-6592]
dc.contributor.orcidHuntly, Brian [0000-0003-0312-161X]
dc.identifier.eissn1471-2407
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMedical Research Council (MR/M010392/1)
pubs.funder-project-idECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (647685)
pubs.funder-project-idWorldwide Cancer Research (14-1069)


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