Unknown

Dataset Information

0

Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma.


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.

SUBMITTER: Beck D 

PROVIDER: S-EPMC4974382 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

altmetric image

Publications

Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma.

Beck Daniel D   Zobel Jenny J   Barber Ruth R   Evans Sian S   Lezina Larissa L   Allchin Rebecca L RL   Blades Matthew M   Elliott Richard R   Lord Christopher J CJ   Ashworth Alan A   Porter Andrew C G AC   Wagner Simon D SD  

The Journal of biological chemistry 20160606 32


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 pr  ...[more]

Similar Datasets

| S-EPMC4136898 | biostudies-literature
| S-EPMC2950064 | biostudies-literature
| S-EPMC8928618 | biostudies-literature
| S-EPMC4086184 | biostudies-literature
| S-EPMC9264875 | biostudies-literature
| S-EPMC6931141 | biostudies-literature
| S-EPMC10167219 | biostudies-literature
| S-EPMC7255460 | biostudies-literature
| S-EPMC2374839 | biostudies-other
| S-EPMC4718674 | biostudies-literature