Chatterjee, T.; Beffert, E.; Dewson, G. S.; Sullivan, D. K.; Anchang, B.; Sears, R. C.; Liefwalker, D.

Both c-MYC and KDM5B are global regulators of gene transcription, cell identity, and master transcription factors in hematopoietic malignancies. In this study we link these two critical factors in a negative feedback loop that controls apoptosis and cell survival. We find the MYC specifically downregulates KDM5B, thereby inhibiting its transcriptional repressive functions. Loss of KDM5B abrogates the cell death response to MYC withdrawal in MYC-dependent cells, indicating KDM5B mediates cell death. We find that KDM5B regulates the MYC network, and specifically demethylates the MYC locus. In summary we have discovered a negative feedback loop between MYC and KDM5B. The MYC-dependent suppression of KDM5B leads to a global increase in H3K4me3 methylation, transcriptional activity, and increase cell survival and tumor progression.