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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3304.
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NEOPLASIA
Comment on Lam et al, page 3701
Signaling crosstalk in DLBCL
Jürgen Ruland
TECHNICAL UNIVERSITY OF MUNICH
In this issue of Blood, Lam and colleagues report synergistic crosstalk between NF- B and the JAK/STAT pathway in a subset of diffuse large B-cell lymphoma (DLBCL) that might have implications for future targeted therapies.
DLBCL is a genetically heterogeneous disease, and many patients are unable to be cured with conventional regimens. A better understanding of the pathobiology of DLBCL is therefore needed to develop novel, rational treatment strategies. Based on gene-expression profiling, Wiestner et al previously classified DLBCL into at least 3 clinically distinct subentities called activated B cell–like DLBCL (ABC DLBCL), germinal center–like DLBCL (GC DLBCL), and a smaller unclassified group.1 Among these, the ABC DLBCL subtype, which is characterized by aberrant activation of the NF-B pathway, shows the most aggressive behavior. NF-B activation in ABC DLBCL depends on the IKK kinase, which receives constitutive signaling input from the CARMA1/BCL10/MALT1 complex2 (see figure). Significantly, IKK/NF-B signaling is essential for the survival of ABC DLBCL and for other lymphomas,3 and small-molecule inhibitors of IKK are lethal for ABC DLBCL cell lines. Treatment of animals with IKK inhibitors resulted in significant toxicities; therefore, clinical development of these inhibitors might be problematic.4
The report by Lam and colleagues in this issue of Blood investigates effector events of NF-B signaling in DLBCL. Using cell line models, they identify IL6 and IL10 as ABC DLBCL–specific NF-B target genes and show that IL-6 and/or IL-10 activate STAT3 via JAK kinases in an autocrine or paracrine manner. These events are associated with high levels of STAT3 phosphorylation and up-regulation of STAT3 mRNA and protein. Activated STAT3 controls a particular gene-expression pattern in ABC DLBCL lines, which allowed the authors to develop a mathematical predictor for STAT3 signaling. Turning to primary tumors, Lam et al used their predictor along with immunohistochemistry to divide ABC DLBCL cases into STAT3-high and STAT3-low subsets. Higher expression of NF-B target genes and a differential control of survival factors, proliferation, and glycolysis regulators were detected in the STAT3-high patient group, indicating functionally relevant crosstalk between STAT3 and NF-B in this ABC DLBCL subset.
Although the STAT3-high and STAT3-low groups do not differ in overall survival, the distinction of the 2 subentities might be significant for the design of future therapies. Lam and colleagues found that blocking STAT3 activation with a JAK kinase inhibitor induced lethality with signs of apoptosis, specifically in ABC DLBCL cells that produced IL-6/IL-10 but not in DLBCL cells that lacked cytokine expression. Notably, IKK inhibitors together with JAK inhibitors induced not only additive but synergistic toxicity in ABC DLBCL cells, potentially via down-regulation of NF-B–dependent cytokine production and a subsequent lowering of the threshold for functional JAK/STAT pathway inhibition. Thus, the findings presented by Lam and colleagues imply that a combination of IKK and JAK inhibitors with lower individual doses and potentially reduced toxicities toward normal cells could become a treatment option for certain ABC DLBCLs. This is certainly an exciting outlook that warrants further investigations, including a detailed in vivo analysis of combined IKK and JAK inhibitor efficiency and toxicity profiles.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests. 
REFERENCES
- Wiestner A and Staudt LM. Towards molecular diagnosis and targeted therapy of lymphoid malignancies. Semin Hematol 2003; 40:296–307.[CrossRef][Medline]
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- Ngo VN, Davis RE, Lamy L, et al. A loss-of-function RNA interference screen for molecular targets in cancer. Nature 2006; 441:106–110.[CrossRef][Medline]
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- Jost PJ and Ruland J. Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood 2007; 109:2700–2707.[Abstract/Free Full Text]
- Nagashima K, Sasseville VG, Wen D, et al. Rapid TNFR1-dependent lymphocyte depletion in vivo with a selective chemical inhibitor of IKKbeta. Blood 2006; 107:4266–4273.[Abstract/Free Full Text]
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Related Article in Blood Online:
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Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-B pathways in subtypes of diffuse large B-cell lymphoma
- Lloyd T. Lam, George Wright, R. Eric Davis, Georg Lenz, Pedro Farinha, Lenny Dang, John W. Chan, Andreas Rosenwald, Randy D. Gascoyne, and Louis M. Staudt
Blood 2008 111: 3701-3713.
[Abstract]
[Full Text]
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