dc.contributor.author | Beck, D | |
dc.contributor.author | Zobel, J | |
dc.contributor.author | Barber, R | |
dc.contributor.author | Evans, S | |
dc.contributor.author | Lezina, L | |
dc.contributor.author | Allchin, RL | |
dc.contributor.author | Blades, M | |
dc.contributor.author | Elliott, R | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Ashworth, A | |
dc.contributor.author | Porter, ACG | |
dc.contributor.author | Wagner, SD | |
dc.date.accessioned | 2017-03-24T13:47:38Z | |
dc.date.issued | 2016-08-05 | |
dc.identifier.citation | The Journal of biological chemistry, 2016, 291 (32), pp. 16686 - 16698 | |
dc.identifier.issn | 0021-9258 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/485 | |
dc.identifier.eissn | 1083-351X | |
dc.identifier.doi | 10.1074/jbc.m116.736868 | |
dc.description.abstract | We 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.format | Print-Electronic | |
dc.format.extent | 16686 - 16698 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Mice, SCID | |
dc.subject | Burkitt Lymphoma | |
dc.subject | Carbazoles | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | STAT3 Transcription Factor | |
dc.subject | Proto-Oncogene Proteins c-bcl-6 | |
dc.subject | Janus Kinase 2 | |
dc.subject | Interleukin-10 Receptor alpha Subunit | |
dc.subject | Lymphoma, Large B-Cell, Diffuse | |
dc.title | Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-05-06 | |
rioxxterms.versionofrecord | 10.1074/jbc.m116.736868 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-08 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | The Journal of biological chemistry | |
pubs.issue | 32 | |
pubs.notes | No 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-status | Published | |
pubs.volume | 291 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Lord, Christopher | |