Synthetic Lethal Screen Demonstrates That a JAK2 Inhibitor Suppresses a BCL6-dependent IL10RA/JAK2/STAT3 Pathway in High Grade B-cell Lymphoma.
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.
From the Department of Cancer Studies, Ernest and Helen Scott Haematology Research Institute, and.
Daniel
D
Beck
Department of Haematology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN.
Jenny
J
Zobel
From the Department of Cancer Studies, Ernest and Helen Scott Haematology Research Institute, and Leicester Diagnostic and Drug Development (LD3) Centre, University of Leicester, Lancaster Road, Leicester LE1 7HB.
Ruth
R
Barber
From the Department of Cancer Studies, Ernest and Helen Scott Haematology Research Institute, and.
Sian
S
Evans
From the Department of Cancer Studies, Ernest and Helen Scott Haematology Research Institute, and.
Larissa
L
Lezina
From the Department of Cancer Studies, Ernest and Helen Scott Haematology Research Institute, and.
Rebecca L
RL
Allchin
Bioinformatics and Biostatistics Analysis Support Hub (B/BASH), University of Leicester, Lancaster Road, Leicester LE1 9HN, and.
Matthew
M
Blades
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom.
Richard
R
Elliott
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom.
Christopher J
CJ
Lord
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom.
Alan
A
Ashworth
Department of Haematology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN.
Andrew C G
AC
Porter
From the Department of Cancer Studies, Ernest and Helen Scott Haematology Research Institute, and sw227@le.ac.uk.
Simon D
SD
Wagner
D000818:Animals; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005663:Furans; D006801:Humans; D053709:Interleukin-10 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000096:biosynthesis* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
C084103:BCL6 protein, human; D002227:Carbazoles; D005663:Furans; D053709:Interleukin-10 Receptor alpha Subunit; D051560:Proto-Oncogene Proteins c-bcl-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C119379:lestaurtinib; C507924:JAK2 protein, human; D053614:Janus Kinase 2
Janus kinase (JAK); interleukin; lymphocyte; lymphoma; signaling