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dc.contributor.authorBeck, D
dc.contributor.authorZobel, J
dc.contributor.authorBarber, R
dc.contributor.authorEvans, S
dc.contributor.authorLezina, L
dc.contributor.authorAllchin, RL
dc.contributor.authorBlades, M
dc.contributor.authorElliott, R
dc.contributor.authorLord, CJ
dc.contributor.authorAshworth, A
dc.contributor.authorPorter, ACG
dc.contributor.authorWagner, SD
dc.date.accessioned2017-03-24T13:47:38Z
dc.date.issued2016-08-05
dc.identifier.citationThe Journal of biological chemistry, 2016, 291 (32), pp. 16686 - 16698
dc.identifier.issn0021-9258
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/485
dc.identifier.eissn1083-351X
dc.identifier.doi10.1074/jbc.m116.736868
dc.description.abstractWe demonstrate the usefulness of synthetic lethal screening of a conditionally BCL6-deficient Burkitt lymphoma cell line, DG75-AB7, with a library of small molecules to determine survival pathways suppressed by BCL6 and suggest mechanism-based treatments for lymphoma. Lestaurtinib, a JAK2 inhibitor and one of the hits from the screen, repressed survival of BCL6-deficient cells in vitro and reduced growth and proliferation of xenografts in vivo BCL6 deficiency in DG75-AB7 induced JAK2 mRNA and protein expression and STAT3 phosphorylation. Surface IL10RA was elevated by BCL6 deficiency, and blockade of IL10RA repressed STAT3 phosphorylation. Therefore, we define an IL10RA/JAK2/STAT3 pathway each component of which is repressed by BCL6. We also show for the first time that JAK2 is a direct BCL6 target gene; BCL6 bound to the JAK2 promoter in vitro and was enriched by ChIP-seq. The place of JAK2 inhibitors in the treatment of diffuse large B-cell lymphoma has not been defined; we suggest that JAK2 inhibitors might be most effective in poor prognosis ABC-DLBCL, which shows higher levels of IL10RA, JAK2, and STAT3 but lower levels of BCL6 than GC-DLBCL and might be usefully combined with novel approaches such as inhibition of IL10RA.
dc.formatPrint-Electronic
dc.format.extent16686 - 16698
dc.languageeng
dc.language.isoeng
dc.publisherAMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectMice, SCID
dc.subjectBurkitt Lymphoma
dc.subjectCarbazoles
dc.subjectXenograft Model Antitumor Assays
dc.subjectSTAT3 Transcription Factor
dc.subjectProto-Oncogene Proteins c-bcl-6
dc.subjectJanus Kinase 2
dc.subjectInterleukin-10 Receptor alpha Subunit
dc.subjectLymphoma, Large B-Cell, Diffuse
dc.titleSynthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma.
dc.typeJournal Article
dcterms.dateAccepted2016-05-06
rioxxterms.versionofrecord10.1074/jbc.m116.736868
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2016-08
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfThe Journal of biological chemistry
pubs.issue32
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.publication-statusPublished
pubs.volume291
pubs.embargo.termsNo embargo
icr.researchteamGene Function
dc.contributor.icrauthorLord, Christopher


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