Constitutive NF-kappaB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas.
B-lymphocyte stimulator (BLyS), a relatively recently recognized member of the tumor necrosis factor ligand family (TNF), is a potent cell-survival factor expressed in many hematopoietic cells. BLyS binds to 3 TNF-R receptors, TACI, BCMA, BAFF-R, to regulate B-cell survival, differentiation, and proliferation. The mechanisms involved in BLYS gene expression and regulation are still incompletely understood. In this study, we examined BLYS gene expression, function, and regulation in B-cell non-Hodgkin lymphoma (NHL-B) cells. Our studies indicate that BLyS is constitutively expressed in aggressive NHL-B cells, including large B-cell lymphoma (LBCL) and mantle cell lymphoma (MCL), playing an important role in the survival and proliferation of malignant B cells. We found that 2 important transcription factors, NF-kappaB and NFAT, are involved in regulating BLyS expression through at least one NF-kappaB and 2 NFAT binding sites in the BLYS promoter. We also provide evidence suggesting that the constitutive activation of NF-kappaB and BLyS in NHL-B cells forms a positive feedback loop associated with lymphoma cell survival and proliferation. Our findings indicate that constitutive NF-kappaB and NFAT activations are crucial transcriptional regulators of the BLyS survival pathway in malignant B cells that could be therapeutic targets in aggressive NHL-B.
Department of Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Lingchen
L
Fu
Yen-Chiu
YC
Lin-Lee
Lan V
LV
Pham
Archito
A
Tamayo
Linda
L
Yoshimura
Richard J
RJ
Ford
D051017:Apoptosis Regulatory Proteins; D053264:B-Cell Activating Factor; D001665:Binding Sites; D002470:Cell Survival; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D050778:NFATC Transcription Factors / Q000378:metabolism* / Q000502:physiology; D011401:Promoter Regions, Genetic; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D053264:B-Cell Activating Factor; D008565:Membrane Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C505719:TNFSF13B protein, human; D014409:Tumor Necrosis Factor-alpha