title: TAL1/SCL is downregulated upon histone deacetylase inhibition in T-cell acute lymphoblastic leukemia cells.
abstract: The transcription factor T-cell acute lymphocytic leukemia (TAL)-1 is a major T-cell oncogene associated with poor prognosis in T-cell acute lymphoblastic leukemia (T-ALL). TAL1 binds histone deacetylase 1 and incubation with histone deacetylase inhibitors (HDACis) promotes apoptosis of leukemia cells obtained from TAL1 transgenic mice. Here, we show for the first time that TAL1 protein expression is strikingly downregulated upon histone deacetylase inhibition in T-ALL cells. This is due to decreased TAL1 gene transcription in cells with native TAL1 promoter, and due to impaired TAL1 mRNA translation in cells that harbor the TAL1(d) microdeletion and consequently express TAL1 under the control of the SCL/TAL1 interrupting locus (SIL) promoter. Notably, HDACi-triggered apoptosis of T-ALL cells is significantly reversed by TAL1 forced overexpression. Our results indicate that the HDACi-mediated apoptotic program in T-ALL cells is partially dependent on their capacity to downregulate TAL1 and provide support for the therapeutic use of HDACi in T-ALL.
authors.affiliation: Cancer Biology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors.forename: B A
authors.initials: BA
authors.lastname: Cardoso
authors.forename: S F
authors.initials: SF
authors.lastname: de Almeida
authors.forename: A B A
authors.initials: AB
authors.lastname: Laranjeira
authors.forename: M
authors.initials: M
authors.lastname: Carmo-Fonseca
authors.forename: J A
authors.initials: JA
authors.lastname: Yunes
authors.forename: P J
authors.initials: PJ
authors.lastname: Coffer
authors.forename: J T
authors.initials: JT
authors.lastname: Barata
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D056572:Histone Deacetylase Inhibitors; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C067143:TAL1 protein, human