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| Item Type: | Preprint |
|---|---|
| Title: | Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability |
| Creators Name: | Barbosa, R.R., Xu, A.Q., D'Andrea, D., Copley, F., Patel, H., Chakravarty, P., Clear, A., Calaminici, M., Janz, M., Zhang, B., Schmidt-Supprian, M., Wang, J., Gribben, J.G., Tooze, R., Fitzgibbon, J., Franzoso, G., Rajewsky, K. and Calado, D.P. |
| Abstract: | NF-κB and MYC are found co-deregulated in human B and plasma-cell cancers. In physiology, NF-κB is necessary for terminal B-to-plasma cell differentiation, whereas MYC repression is required. It is thus unclear if NF-κB/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-κB/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-κB 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. SIGNIFICANCE: Our studies improve the understanding of cancer pathogenesis by demonstrating that co-deregulation of NF-κB 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-κB 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. |
| Keywords: | NF-kB, MYC, IL6, B-Cell, Plasma-Cell, Plasmablast, B-Cell Terminal Differentiation, Diffuse Large B-Cell Lymphoma, Plasmablastic Lymphoma, Multiple Myeloma, Phenotypic Stability, Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2020.04.12.038414 |
| Date: | 13 April 2020 |
| Official Publication: | https://doi.org/10.1101/2020.04.12.038414 |
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