Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma.
J Biol Chem, 2016/08/05;291(32):16686-98.
Beck D[1], Zobel J[2], Barber R[3], Evans S[1], Lezina L[1], Allchin RL[1], Blades M[4], Elliott R[5], Lord CJ[5], Ashworth A[5], Porter AC[2], Wagner SD[6]
Affiliations
PMID: 27268052DOI: 10.1074/jbc.M116.736868
Impact factor: 5.486
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.
Keywords: Janus kinase (JAK); interleukin; lymphocyte; lymphoma; signaling
MeSH terms
Animals; Burkitt Lymphoma; Carbazoles; Cell Line, Tumor; Furans; Humans; Interleukin-10 Receptor alpha Subunit; Janus Kinase 2; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, SCID; Proto-Oncogene Proteins c-bcl-6; STAT3 Transcription Factor; Xenograft Model Antitumor Assays
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