title: BET bromodomain inhibition rescues erythropoietin differentiation of human erythroleukemia cell line UT7.
abstract: Malignant transformation is a multistep process requiring oncogenic activation, promoting cellular proliferation, frequently coupled to inhibition of terminal differentiation. Consequently, forcing the reengagement of terminal differentiation of transformed cells coupled or not with an inhibition of their proliferation is a putative therapeutic approach to counteracting tumorigenicity. UT7 is a human leukemic cell line able to grow in the presence of IL3, GM-CSF and Epo. This cell line has been widely used to study Epo-R/Epo signaling pathways but is a poor model for erythroid differentiation. We used the BET bromodomain inhibition drug JQ1 to target gene expression, including that of c-Myc. We have shown that only 2 days of JQ1 treatment was required to transitory inhibit Epo-induced UT7 proliferation and to restore terminal erythroid differentiation. This study highlights the importance of a cellular erythroid cycle break mediated by c-Myc inhibition before initiation of the erythropoiesis program and describes a new model for BET bromodomain inhibitor drug application.
authors.affiliation: CEA, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Goupille
authors.forename: Tipparat
authors.initials: T
authors.lastname: Penglong
authors.forename: Carine
authors.initials: C
authors.lastname: Lefèvre
authors.forename: Marine
authors.initials: M
authors.lastname: Granger
authors.forename: Zahra
authors.initials: Z
authors.lastname: Kadri
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.forename: Leila
authors.initials: L
authors.lastname: Maouche-Chrétien
authors.forename: Philippe
authors.initials: P
authors.lastname: Leboulch
authors.forename: Stany
authors.initials: S
authors.lastname: Chrétien
mesh_terms: D001381:Azepines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D041905:Erythroid Cells / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology*; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D014230:Triazoles; D004921:Erythropoietin