ATF6 Identification Sensitizes B-Cell Precursor Acute Lymphoblastic Leukemia Cells to Doxorubicin.
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OBJECTIVE: Activating transcription factor 6 (ATF6) is a part of the unfolded protein response (UPR) system, which plays an important role in regulating endoplasmic reticulum stress. The overexpression of ATF6 has been reported in various malignancies; however, its expression and functional significance in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are poorly understood. METHODS: Bone marrow samples from 69 pediatric patients with ALL (48 newly diagnosed, 21 relapsed) and peripheral blood/bone marrow samples from 29 nonleukemic healthy children (controls) were collected. To investigate the effect of ATF6 inhibition on the viability of BCP-ALL derived cell lines, NALM-6 and SUP-B15 cells were treated with the ATF6 inhibitor Ceapin-A7 both alone and in combination with doxorubicin. Apoptosis was quantitatively assessed using flow cytometry. The expression levels of ATF6, BCL-2 family members, and ATF6 target genes were determined by qRT-PCR, and the protein levels of ATF6, caspase-3, PARP, cell cycle regulators by Western blot analysis. RESULTS: Our results revealed that the ATF6 expression was higher in pediatric patients with relapsed ALL than in newly diagnosed patients. Furthermore, inhibition of ATF6 with Ceapin-A7 enhanced doxorubicin-induced apoptosis in the BCP-ALL cell lines NALM-6 and SUP-B15. Upon inhibition of ATF6, both BCP-ALL cell lines were arrested at the G1 phase of the cell cycle. Combined treatment altered the expression of apoptosis-related and cell cycle regulatory genes and proteins, and ATF6 target genes were upregulated by Ceapin-A7 alone but attenuated in the combined treatment group. CONCLUSION: ATF6 inhibition combined with doxorubicin represents a promising therapeutic strategy for enhancing apoptosis in BCP-ALL cells.