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Although we previously reported that the self-renewal of leukemia-initiating cells of B-lineage acute lymphoblastic leukemia (B-ALL LICs) was regulated by  β -Arrestin1, a multiple-function protein, the cellular senescence is critical for LICs fate and leukemia progress, and worthy for further investigation. Here we found that depletion of  β-Arrestin1  extended the population doubling time and the percentage of senile cells, the signatures of cellular senescence, of B-ALL LICs. Moreover, lack of  β-Arrestin1  enhanced the expression of proteins (CBX, HIRA) and genes ( P53 ,  P16 ) related to senescence in leukemic Reh cells and B-ALL-LICs-derived leukemic mice. Further results showed that loss of  β-Arrestin1  induced senescence of Reh cells through mediating  hTERT -telomerase-telomere axis, which was reversed by BIBR1532, the telomerase activity inhibitor. Importantly, depletion of  β-Arrestin1  decreased the binding of Sp1 to  hTERT  promoter at the region of −28 to −36 bp. The anti-sense oligonucleotide of this key region downregulated the transcription of  hTERT  and aggravated the senescence of Reh cells. Further data demonstrated that the depleted  β-Arrestin1  reduced the interaction of P300 with Sp1, thus to reduce Sp1 binding to  hTERT  promoter, downregulate  hTERT  transcription, decrease telomerase activity, shorten telomere length, and promote Reh cell senescence. Interestingly, the percentage of senile cells in B-ALL LICs was decreased, which was negatively correlated to good prognosis and  β-Arrestin1  mRNA expression in childhood B-ALL patients. Our study shed a light on the senescence of B-ALL LICs and is regulated by  β-Arrestin1 , providing the potential therapeutic target of leukemia by promoting cellular senescence with a key region of  hTERT  promoter.

cell death and disease

The cellular senescence of leukemia-initiating cells from acute lymphoblastic leukemia is postponed by β-Arrestin1 binding with P300-Sp1 to regulate hTERT transcription