The AP-1 transcription factor, Fra1, regulates apoptosis in the acute promyelocytic leukemia (APL) cells

Abstract

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) associated with the accumulation of fusion gene of PML/RARA. All-trans retinoic acid (ATRA) has been used in APL patients for inducing leukemic cell differentiation through the PML-RARαdegradation. However, it has been known to have a limitation in therapeutic efficacy due to the resistance to ATRA. Fos-related antigen 1 (Fra-1), a member of the activating protein 1 (AP-1) family, has been reported to regulate the differentiation of osteoclasts, macrophages and adipocytes. AP-1 family members are known to control the ATRA-induced differentiation in the APL, but the correlation with Fra-1 is poorly understood. In this study, we investigated the effect of ATRA on Fra-1 expression in human APL cell line. Fra-1 expression was significantly downregulated by ATRA treatment. Inhibition of Fra-1 markedly affected the expression of differentiation-related genes, such as C/EBPαand PU.1. Nevertheless, knockdown of Fra-1 did not change differentiation of APL. Interestingly, Fra-1 overexpression induced an increase of CD38 negative cells that are known to be reduced by ATRA and related to drug resistance. We found that ATRA induced CD38 expression through the inhibition of the Fra-1 expression on HL-60 cells. Actually, knockdown of Fra-1 significantly enhanced paclitaxel-induced apoptosis in APL cells. These results indicate that the transcription factor Fra-1 might negatively control apoptosis and positively regulate drug resistance in HL-60 cells. In summary, these findings suggest that Fra-1 could be a therapeutic target for combination therapy that affects drug resistance and suppresses apoptosis in APL cells. Eur. J. Immunol. 2019. 49 (Suppl. 3): 1–2223