Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-κB pathways in subtypes of diffuse large B-cell lymphoma
Open Access
- 1 April 2008
- journal article
- Published by American Society of Hematology in Blood
- Vol. 111 (7), 3701-3713
- https://doi.org/10.1182/blood-2007-09-111948
Abstract
The activated B cell–like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL) is characterized by constitutive activation of the nuclear factor-κB (NF-κB) pathway. In this study, we showed that the NF-κB pathway induced the expression of the cytokines interleukin (IL)-6 and IL-10 in ABC DLBCL cell lines, which also have high levels of total and phosphorylated signal transducer and activator of transcription (STAT) 3 protein, suggesting autocrine signaling. Using RNA interference for STAT3, we defined a gene expression signature of IL-6 and IL-10 signaling through STAT3. Based on this signature, we constructed a molecular predictor of STAT3 signaling that defined a subset of ABC DLBCL tumors with high expression of STAT3, IL-6, and/or IL-10 and their downstream targets. Although the STAT3-high and STAT3-low subsets had equivalent expression of genes that distinguish ABC DLBCL from germinal center B cell–like DLBCL, STAT3-high ABC DLBCLs had higher expression of signatures that reflected NF-κB activity, proliferation, and glycolysis. A small-molecule inhibitor of Janus kinase signaling, which blocked STAT3 signature expression, was toxic only for ABC DLBCL lines and synergized with an inhibitor of NF-κB signaling. These findings suggest that the biological interplay between the STAT3 and NF-κB pathways may be exploited for the treatments of a subset of ABC DLBCLs.Keywords
This publication has 63 references indexed in Scilit:
- Role of JAK2 in the pathogenesis and therapy of myeloproliferative disordersNature Reviews Cancer, 2007
- Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphomaLeukemia, 2007
- Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFκBGenes & Development, 2007
- The Bcl-2 apoptotic switch in cancer development and therapyOncogene, 2007
- Erlotinib Effectively Inhibits JAK2V617F Activity and Polycythemia Vera Cell GrowthPublished by Elsevier BV ,2007
- Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironmentNature Reviews Immunology, 2007
- The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralizedCancer Cell, 2006
- A loss-of-function RNA interference screen for molecular targets in cancerNature, 2006
- STATs in oncogenesisOncogene, 2000
- Distinct types of diffuse large B-cell lymphoma identified by gene expression profilingNature, 2000