title: Growth factor independence 1 antagonizes a p53-induced DNA damage response pathway in lymphoblastic leukemia.
abstract: Most patients with acute lymphoblastic leukemia (ALL) fail current treatments highlighting the need for better therapies. Because oncogenic signaling activates a p53-dependent DNA damage response and apoptosis, leukemic cells must devise appropriate countermeasures. We show here that growth factor independence 1 (Gfi1) can serve such a function because Gfi1 ablation exacerbates p53 responses and lowers the threshold for p53-induced cell death. Specifically, Gfi1 restricts p53 activity and expression of proapoptotic p53 targets such as Bax, Noxa (Pmaip1), and Puma (Bbc3). Subsequently, Gfi1 ablation cures mice from leukemia and limits the expansion of primary human T-ALL xenografts in mice. This suggests that targeting Gfi1 could improve the prognosis of patients with T-ALL or other lymphoid leukemias.
authors: Institut de recherches cliniques de Montréal (IRCM), 110 Avenue des Pins Ouest, Montréal, Quebec H2W 1R7, Canada.
authors: Cyrus
authors: C
authors: Khandanpour
authors: James D
authors: JD
authors: Phelan
authors: Lothar
authors: L
authors: Vassen
authors: Judith
authors: J
authors: Schütte
authors: Riyan
authors: R
authors: Chen
authors: Shane R
authors: SR
authors: Horman
authors: Marie-Claude
authors: MC
authors: Gaudreau
authors: Joseph
authors: J
authors: Krongold
authors: Jinfang
authors: J
authors: Zhu
authors: William E
authors: WE
authors: Paul
authors: Ulrich
authors: U
authors: Dührsen
authors: Bertie
authors: B
authors: Göttgens
authors: H Leighton
authors: HL
authors: Grimes
authors: Tarik
authors: T
authors: Möröy
mesh_terms: D000818:Animals; D017209:Apoptosis; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; C497761:NOTCH1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051881:Receptor, Notch1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53