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Title: Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma
Authors: Beck, Daniel
Zobel, Jenny
Barber, Ruth
Evans, Sian
Lezina, Larissa
Allchin, Rebecca L.
Blades, Matthew
Elliott, Richard
Lord, Christopher J.
Ashworth, Alan
Porter, Andrew C. G.
Wagner, Simon D.
First Published: 6-Jun-2016
Publisher: American Society for Biochemistry and Molecular Biology
Citation: Journal of Biological Chemistry, 2016, 291 (32), pp. 16686-16698
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.
DOI Link: 10.1074/jbc.M116.736868
ISSN: 0021-9258
eISSN: 1083-351X
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © The American Society for Biochemistry and Molecular Biology, Inc., 2016 Deposited with reference to the publisher’s open access archiving policy.
Description: The file associated with this record is embargoed until 12 months after the date of publication. The final published version may be available through the links above.
Appears in Collections:Published Articles, Dept. of Cancer Studies and Molecular Medicine

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