Alternative and canonical NF-kB pathways DNA-binding hierarchies networks define Hodgkin lymphoma and Non-Hodgkin diffuse large B Cell lymphoma respectively
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.
KeywordsHodgkin lymphoma Non-Hodgkin lymphoma DLBCL Rel-B NF-kB alternative pathway Germinal center-derived lymphomas
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.
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