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

ABSTRACT: Although we previously reported that the self-renewal of leukemia-initiating cells of B-lineage acute lymphoblastic leukemia (B-ALL LICs) was regulated by ?-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 ?-Arrestin1 extended the population doubling time and the percentage of senile cells, the signatures of cellular senescence, of B-ALL LICs. Moreover, lack of ?-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 ?-Arrestin1 induced senescence of Reh cells through mediating hTERT-telomerase-telomere axis, which was reversed by BIBR1532, the telomerase activity inhibitor. Importantly, depletion of ?-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 ?-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 ?-Arrestin1 mRNA expression in childhood B-ALL patients. Our study shed a light on the senescence of B-ALL LICs and is regulated by ?-Arrestin1, providing the potential therapeutic target of leukemia by promoting cellular senescence with a key region of hTERT promoter.

SUBMITTER: Liu S 

PROVIDER: S-EPMC5603829 | biostudies-other | 2017 Apr

REPOSITORIES: biostudies-other