Because ICN1 and ICN3 can substitute for one another in Notch-dependent T-ALL cells and because there is no evidence to date that Notch complexes can bind and open repressed chromatin, we speculate that the observed differences result either from cell-line specific differences in factors operating upstream of Notch that regulate chromatin states, or from variation in the capacity of the divergent “TAD” regions of Notch1 and Notch3 to recruit histone acetyltransferases such as p300 in concert with Mastermind-like co-activators. This evidence concerns the gene NOTCH1 and acute lymphoblastic leukemia.