Molecular impact of selective NFKB1 and NFKB2 signaling on DLBCL phenotype

X. Guo, J. L. Koff, A. B. Moffitt, M. Cinar, S. Ramachandiran, Z. Chen, J. M. Switchenko, M. Mosunjac, S. G. Neill, K. P. Mann, M. Bagirov, Y. Du, Y. Natkunam, H. J. Khoury, M. R. Rossi, W. Harris, C. R. Flowers, I. S. Lossos, L. H. Boise, S. S. DaveJ. Kowalski, L. Bernal-Mizrachi

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Diffuse large B-cell lymphoma (DLBCL) has been categorized into two molecular subtypes that have prognostic significance, namely germinal center B-cell like (GCB) and activated B-cell like (ABC). Although ABC-DLBCL has been associated with NF-ΰ B activation, the relationships between activation of specific NF-ΰ B signals and DLBCL phenotype remain unclear. Application of novel gene expression classifiers identified two new DLBCL categories characterized by selective p100 (NF-ΰ B2) and p105 (NF-ΰ B1) signaling. Interestingly, our molecular studies showed that p105 signaling is predominantly associated with GCB subtype and histone mutations. Conversely, most tumors with p100 signaling displayed ABC phenotype and harbored ABC-associated mutations in genes such as MYD88 and PIM1. In vitro, MYD88 L265P mutation promoted p100 signaling through TAK1/IKKα and GSK3/Fbxw7a pathways, suggesting a novel role for this protein as an upstream regulator of p100. p100 signaling was engaged during activation of normal B cells, suggesting p100's role in ABC phenotype development. Additionally, silencing p100 in ABC-DLBCL cells resulted in a GCB-like phenotype, with suppression of Blimp, IRF4 and XBP1 and upregulation of BCL6, whereas introduction of p52 or p100 into GC cells resulted in differentiation toward an ABC-like phenotype. Together, these findings identify specific roles for p100 and p105 signaling in defining DLBCL molecular subtypes and posit MYD88/p100 signaling as a regulator for B-cell activation.

Original languageEnglish (US)
Pages (from-to)4224-4232
Number of pages9
JournalOncogene
Volume36
Issue number29
DOIs
StatePublished - Jul 20 2017
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Guo, X., Koff, J. L., Moffitt, A. B., Cinar, M., Ramachandiran, S., Chen, Z., Switchenko, J. M., Mosunjac, M., Neill, S. G., Mann, K. P., Bagirov, M., Du, Y., Natkunam, Y., Khoury, H. J., Rossi, M. R., Harris, W., Flowers, C. R., Lossos, I. S., Boise, L. H., ... Bernal-Mizrachi, L. (2017). Molecular impact of selective NFKB1 and NFKB2 signaling on DLBCL phenotype. Oncogene, 36(29), 4224-4232. https://doi.org/10.1038/onc.2017.90