Our data revealed that depletion of β-Arrestin1 facilitated cell senescence of B-ALL LICs in vivo and in vitro, by regulating hTERT transcription through inducing P300-Sp1 interaction at −28 to −36 bp of hTERT promoter, which was further illustrated by the data from clinical samples that decreased senile cells and elevated expression of β-Arrestin1 predicted poor prognosis in B-ALL, providing the potential therapeutic target of leukemia by promoting cellular senescence. The gene discussed is SP1; the disease is leukemia.