NFκB regulates p21 expression and controls DNA damage-induced leukemic differentiation

DNA damage exposure is a major modifier of cell fate in both normal and cancer tissues. In response to DNA damage, myeloid leukemia cells activate a poorly understood terminal differentiation process. Here, we show that the NF kappa B pathway directly activates expression of the proliferation inhibitor p21 in response to DNA damage in myeloid leukemia cells. In order to understand the role of this unexpected regulatory event, we ablated the NF kappa B binding site we identified in the p21 promoter, using CRISPR/Cas9-mediated genome editing. We found that NF kappa B-mediated p21 activation controls DNA damage-induced myeloid differentiation. Our results uncover a p53-independent pathway for p21 activation involved in controlling hematopoietic cell fate.