Concerns that expression of NOTCH-ICD exerts ‘supra-pathophysiological’ effects of NOTCH1, not seen with PEST domain deleted endogenous NOTCH1, were overcome by our quantitative analyses of target gene expression, reverse regulation of PD-L1 and HLA-DR by GSI treatment of NOTCH1-mutated CLL and numerous in vivo analyses. The gene discussed is CD274; the disease is B-cell chronic lymphocytic leukemia.