title: TLX homeodomain oncogenes mediate T cell maturation arrest in T-ALL via interaction with ETS1 and suppression of TCRα gene expression.
abstract: Acute lymphoblastic leukemias (ALLs) are characterized by multistep oncogenic processes leading to cell-differentiation arrest and proliferation. Specific abrogation of maturation blockage constitutes a promising therapeutic option in cancer, which requires precise understanding of the underlying molecular mechanisms. We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement. TLX1/TLX3 abrogation or enforced TCRαβ expression leads to TCRα rearrangement and apoptosis. Importantly, the autoextinction of clones carrying TCRα-driven TLX1 expression supports TLX "addiction" in TLX-positive leukemias and provides further rationale for targeted therapy based on disruption of TLX1/TLX3.
authors.affiliation: Department of Hematologye, Université de Médecine Paris Descartes Sorbonne Cité, Centre National de la Recherche Scientifique (CNRS), France.
authors.forename: Saïda
authors.initials: S
authors.lastname: Dadi
authors.forename: Sandrine
authors.initials: S
authors.lastname: Le Noir
authors.forename: Dominique
authors.initials: D
authors.lastname: Payet-Bornet
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lhermitte
authors.forename: Joaquin
authors.initials: J
authors.lastname: Zacarias-Cabeza
authors.forename: Julie
authors.initials: J
authors.lastname: Bergeron
authors.forename: Patrick
authors.initials: P
authors.lastname: Villarèse
authors.forename: Elodie
authors.initials: E
authors.lastname: Vachez
authors.forename: Willem A
authors.initials: WA
authors.lastname: Dik
authors.forename: Corinne
authors.initials: C
authors.lastname: Millien
authors.forename: Isabelle
authors.initials: I
authors.lastname: Radford
authors.forename: Els
authors.initials: E
authors.lastname: Verhoeyen
authors.forename: François-Loïc
authors.initials: FL
authors.lastname: Cosset
authors.forename: Arnaud
authors.initials: A
authors.lastname: Petit
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Salvatore
authors.initials: S
authors.lastname: Spicuglia
authors.forename: Anton W
authors.initials: AW
authors.lastname: Langerak
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Macintyre
authors.forename: Bertrand
authors.initials: B
authors.lastname: Nadel
authors.forename: Pierre
authors.initials: P
authors.lastname: Ferrier
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
mesh_terms: D017209:Apoptosis; D001665:Binding Sites; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D019673:Genes, T-Cell Receptor alpha; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D017434:Protein Structure, Tertiary; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C494041:ETS1 protein, human; D018398:Homeodomain Proteins; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; C489494:TLX3 protein, human; C071250:TLX1 protein, human