Alternative and canonical NF-kB pathways DNA-binding hierarchies networks define Hodgkin lymphoma and Non-Hodgkin diffuse large B Cell lymphoma respectively

  • Angélica María Gamboa-Cedeño
  • Mariángeles Castillo
  • Wenming Xiao
  • Thomas A. Waldmann
  • Stella Maris RanuncoloEmail author
Original Article – Cancer Research



Despite considerable evidence that supports the NF-kB role in the immune system and lymphomagenesis, it is unclear whether specific NF-kB dimers control a particular set of genes that account for their biological functions. Our previous work showed that Hodgkin Lymphoma (HL) is unique, among germinal center (GC)-derived lymphomas, with respect to its dependency on Rel-B to survive. In contrast, diffuse large B-Cell lymphoma (DLBCL) including both Activated B-Cell-Like and Germinal Center B-Cell-Like, requires cREL and Rel-A to survive and it is not affected by Rel-B depletion. These findings highlighted the activity of specific NF-kB subunits in different GC-derived lymphomas.


Sequenced chromatin immunoprecipitated DNA fragments (ChIP-Seq) analysis revealed an extensive NF-kB DNA-binding network in DLBCL and HL. The ChIP-Seq data was merged with microarray analysis following the Rel-A, Rel-B or cRel knockdown to determine effectively regulated genes.


Downstream target analysis showed enrichment for cell cycle control, among other signatures. Rel-B and cRel controlled different genes within the same signature in HL and DLBCL, respectively. BCL2 was exclusively controlled by Rel-B in HL. Both mRNA and protein levels decreased following Rel-B depletion meanwhile there was no change upon cRel knock-down. BCL2 exogenous expression partially rescued the death induced by decreased Rel-B in HL cells.


The Rel-B hierarchical network defined HL and the cRel hierarchical network characterized DLBCL. Each Rel member performs specific functions in distinct GC-derived lymphomas. This result should be considered for the development of targeted therapies that are aimed to selectively inhibit individual NF-kB dimers.


Hodgkin lymphoma Non-Hodgkin lymphoma DLBCL Rel-B NF-kB alternative pathway Germinal center-derived lymphomas 


Author contributions

AMGC and MC performed experiments, WX analyzed the ChIP-Seq data and developed the algorithm for this purpose. TAW discussed results. SMR performed experiments, analyzed data, discussed results and wrote the manuscript.


Instituto Universitario del Hospital Italiano (IUHI), Buenos Aires, Argentina. Fundación para el Progreso de la Medicina (FPM), Ciudad de Córdoba, Córdoba, Argentina. Intramural Program of the National Cancer Institute (NCI), National Institutes of Health (NIH).

Compliance with ethical standards

Conflict of interests

The authors declare no competing interests.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB), CONICET-Instituto Universitario del Hospital Italiano-Hospital Italiano de Buenos AiresBuenos AiresArgentina
  2. 2.Center for Information Technology, National Institutes of Health (NIH)BethesdaUSA
  3. 3.Lymphoid Malignancies Branch, Center for Cancer Research (CCR), NCI-NIHBethesdaUSA
  4. 4.Departamento de Histología y Biología Celular, Facultad de MedicinaUniversidad de Buenos AiresBuenos AiresArgentina
  5. 5.National Council of Scientific and Technological Research (CONICET)Buenos AiresArgentina

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