Journal
BLOOD
Volume 117, Issue 1, Pages 200-210Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-06-290437
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Funding
- National Cancer Institute [CA-R01-100836]
- Cancer Center [CA-16672-26]
- Lymphoma Research Foundation of America
- Leukemia & Lymphoma Society [LSS 6087-08]
- Odyssey program
- The University of Texas M. D. Anderson Cancer Center
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Aberrant nuclear factor kappa B (NF-kappa B) signaling has been found to be of particular importance in diffuse, large B-cell lymphoma (DLBCL) cell survival and proliferation. Although the canonical NF-kappa B signaling pathway has been studied in some detail, activation of the alternative NF-kappa B pathway in DLBCL is not well characterized. Important insights into the regulation of the alternative NF-kappa B pathway in B lymphocytes has recently revealed the regulatory importance of the survival kinase NIK (NF-kappa B-inducing kinase) in genetically engineered murine models. Our studies demonstrate that both the canonical and alternative NF-kappa B pathways are constitutively activated in DLBCL. We also demonstrate that NIK kinase aberrantly accumulates in DLBCL cells due to constitutive activation of B-cell activation factor (BAFF)-R (BR3) through interaction with autochthonous B-lymphocyte stimulator (BLyS) ligand in DLBCL cells. Activation of BR3 in DLBCL induces recruitment and degradation of tumor necrosis factor receptor-associated factor 3, which results in NIK kinase accumulation, I kappa B alpha phosphorylation, and NF-kappa B p100 processing, thereby resulting in continuous activation of both NF-kappa B pathways in DLBCL cells, leading to autonomous lymphoma cell growth and survival. These results further elucidate mechanisms involved in abnormal NF-kappa B activation in DLBCL, and should contribute to better future therapeutic approaches for patients with DLBCL. (Blood. 2011;117(1):200-210)
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