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 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.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common tumor in children under age 15
On the basis of our previous report that β-Arrestin[1] regulated the self-renewal of B-lineage acute lymphoblastic leukemia (B-ALL) LICs5 and the cellular senescence is another critical factor for leukemia-initiating cells (LICs) and leukemia progress;[4] here we further investigate whether the cellular
The results showed that only progenitor Reh cells had the similar pattern of cellular senescence and β-Arrestin[1] expression with that of the LICs from B-ALL patients
Summary
Acute lymphoblastic leukemia (ALL) is the most common tumor in children under age 15. Mainly induced by stress, oncogenes, and tumor suppressors,[5] has been increasingly demonstrated to be critical for the development of several kinds of leukemia.[6] Replicative senescence is called telomereinduced senescence, primarily due to shortened telomere, and the senescence is present in Ph+ CML7 and chronic lymphocytic leukemia (CLL).[8] Most of the human cancers have acquired mechanisms to maintain telomeres, generally through high expression of telomerase. Our data revealed that depletion of β-Arrestin[1] 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-Arrestin[1] predicted poor prognosis in B-ALL, providing the potential therapeutic target of leukemia by promoting cellular senescence
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