title: Leukemia-initiating cell activity requires calcineurin in T-cell acute lymphoblastic leukemia.
abstract: Despite their initial efficient response to induction chemotherapy, relapse remains frequent in patients with T-cell acute lymphoblastic leukemia (T-ALL), an aggressive malignancy of immature T-cell progenitors. We previously reported sustained calcineurin (Cn) activation in human lymphoid malignancies, and showed that Cn inhibitors have antileukemic effects in mouse models of T-ALL. It was unclear, however, from these studies whether these effects resulted from Cn inhibition in leukemic cells themselves or were an indirect consequence of impaired Cn function in the supportive tumor microenvironment. We thus generated a Notch (intracellular Notch 1, ICN1)-induced T-ALL mouse model, in which conditional Cn genetic deletion is restricted to leukemic cells. Ex vivo, Cn deletion altered the adhesive interactions between leukemic cells and their supportive stroma, leukemic cell survival, proliferation, migration and clonogenic potential. In vivo, Cn activation was found to be critical for leukemia initiating/propagating cell activity as demonstrated by the failure of Cn-deficient leukemic cells to transplant the disease to syngeneic recipient mice. Importantly, combination of vincristine treatment with Cre-mediated Cn ablation cooperated to induce long-term remission of ICN1-induced T-ALL. These findings indicate that Cn is a promising target in T-ALL relapse prevention, and call for clinical trials incorporating Cn inhibitors during consolidation therapy.
authors.affiliation: 1] Institut Curie, Centre Universitaire, Orsay, France [2] Centre National de la Recherche Scientifique UMR 3306, Orsay, France [3] Institut National de la Santé et de la Recherche Médicale U1005, Orsay, France.
authors.forename: S
authors.initials: S
authors.lastname: Gachet
authors.forename: E
authors.initials: E
authors.lastname: Genescà
authors.forename: D
authors.initials: D
authors.lastname: Passaro
authors.forename: M
authors.initials: M
authors.lastname: Irigoyen
authors.forename: H
authors.initials: H
authors.lastname: Alcalde
authors.forename: C
authors.initials: C
authors.lastname: Clémenson
authors.forename: S
authors.initials: S
authors.lastname: Poglio
authors.forename: F
authors.initials: F
authors.lastname: Pflumio
authors.forename: A
authors.initials: A
authors.lastname: Janin
authors.forename: C
authors.initials: C
authors.lastname: Lasgi
authors.forename: S
authors.initials: S
authors.lastname: Dodier
authors.forename: M
authors.initials: M
authors.lastname: Soyer
authors.forename: G
authors.initials: G
authors.lastname: Duménil
authors.forename: J
authors.initials: J
authors.lastname: Ghysdael
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D065095:Calcineurin Inhibitors; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000503:physiopathology*; D059016:Tumor Microenvironment
chemical_list: D065095:Calcineurin Inhibitors; D019703:Calcineurin