Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability

NF-{kappa}B and MYC are found co-deregulated in human B and plasma-cell cancers. In physiology, NF-{kappa}B is necessary for terminal B-to-plasma cell differentiation, whereas MYC repression is required. It is thus unclear if NF-{kappa}B/MYC co-deregulation is developmentally compatible in carcinogenesis and/or impacts cancer cell differentiation state, possibly uncovering unique sensitivities. Using a mouse system to trace cell lineage and oncogene activation we found that NF-{kappa}B/MYC co-deregulation originated cancers with a plasmablast-like phenotype, alike human plasmablastic-lymphoma and was linked to t(8;14)[MYC-IGH] multiple myeloma. Notably, in contrast to NF-{kappa}B or MYC activation alone, co-deregulation rendered cells addicted to IL6 for survival and phenotypic stability. We propose that conflicting oncogene-driven differentiation pressures can be accommodated at a cost in poorly-differentiated cancers. SignificanceOur studies improve the understanding of cancer pathogenesis by demonstrating that co-deregulation of NF-{kappa}B and MYC synergize in forming a cancer with a poorly-differentiated state. The cancers in the mouse system share features with human Plasmablastic lymphoma that has a dismal prognosis and no standard of care, and with t(8;14)[MYC-IGH] Multiple myeloma, which is in overall resistant to standard therapy. Notably, we found that NF-{kappa}B and MYC co-deregulation uniquely render cells sensitive to IL6 deprivation, providing a road-map for patient selection. Because of the similarity of the cancers arising in the compound mutant mouse model with that of human Plasmablastic lymphoma and t(8;14)[MYC-IGH] Multiple myeloma, this model could serve in preclinical testing to investigate novel therapies for these hard-to-treat diseases. HighlightsO_LINF-{kappa}B and MYC co-activation originates (pre)plasmablast-like cancer C_LIO_LINF-{kappa}B/MYC+ renders cancer cells addicted to IL6 for survival and phenotypic stability C_LIO_LINF-{kappa}B/MYC+ cancers are alike a fraction of human plasmablastic lymphoma C_LIO_LIt(8;14)[MYC-IGH] multiple myeloma is linked to a NF-{kappa}B/MYC co-activation signature C_LI