High expression of PSF1 promotes drug resistance and cell cycle transit in leukemia cells

概要

〔目 的(Purpose) 〕
Escape of cancer cells from chemotherapy is a problem in the management of cancer patients. Chemotherapy resistance research has mainly been focused on the heterogeneity of cancer cells, multiple gene mutations, and quiescence of malignant cancer cells. However, some studies have indicated that interactions between cancer cells and vascular cells promote resistance to chemotherapy. Previous study shown that PSF1+/- mice exhibit reduced HSC proliferation after bone marrow (BM) ablation with anti-cancer drugs. These data indicate that PSF1 is essential for acute cel1 proliferation, especially of undifferentiated/progenitor cells. Moreover, PSF1 not only plays a crucial role under physiological conditions, but is also highly expressed in cancer cell proliferation. Therefore. PSF1 may represent a prognostic marker in several types of cancers. However, it remains unknown whether PSF1 levels are associated with chemo-resistance.

〔方法ならびに成績(Methods/Results)〕
We established mouse leukemia models using the cell1ines THP-1 or MEG-1, these are derived from acute and chronic myeloid leukemias, respectively, and highly express DNA replication factor PSF1, a member of GINS complex. Intravenous injection of these leukemia cells results in their occupation of the mouse BM and constitutes an animal model of human leukemia. Using this mouse model, we investigated whether PSF1hish cells localize near blood vessels in BM and manifest chemo-resistance. For subsequent in vitro analysis of chemo-resistance in these leukemia cells, we conducted experiments to knock-down PSF1 to determine whether it is involved in cell cycle progression and apoptosis.

We found that after anti-cancer drug administration, surviving GFP-positive leukemia cells in the BM were located adjacent to blood vessels, as previously reported in a subcutaneous solid tumor transplantation model. Treating THP-1 and MEG-1 cells with anti-cancer drugs in vitro revealed that those most strongly expressing PSF1 were most chemo-resistant, suggesting that PSF1 induces not only cell cycle progression but also facilitates cell survival. Indeed, when PSF1 expression was suppressed by shRNA. the growth rate was reduced and apoptosis enhanced in both cell lines.

〔総 括(Conclusion)〕
In the present study, we treated mice with an anti-cancer drug in a leukemia transplantation model, and found that cancer cells strongly expressing PSF1, a DNA initiation regulating factor, localized to vascular areas and were drug-resistant. These findings suggest that the vascular niche might play a critical role in chemotherapy resistance. Moreover. PSF1 might act as a potential therapeutic target to enhance the effect of chemotherapy and prognosis.