title: An immediate transcriptional signature associated with response to the histone deacetylase inhibitor Givinostat in T acute lymphoblastic leukemia xenografts.
abstract: Despite some success with certain hematological malignancies and in contrast with the strong pro-apoptotic effects measured in vitro, the overall response rate of acute lymphoblastic leukemia (ALL) to histone deacetylase inhibitors (HDACis) is low. With the aim to improve the understanding of how HDACis work in vivo, we investigated the therapeutic efficacy of the clinically approved HDACi Givinostat in a collection of nine pediatric human T-ALL engrafted systemically in NOD/SCID mice. We observed highly heterogeneous antileukemia responses to Givinostat, associated with reduction of the percentage of infiltrating blasts in target organs, induction of apoptosis and differentiation. These effects were not associated with the T-ALL cytogenetic subgroup. Transcriptome analysis disclosed an immediate transcriptional signature enriched in genes involved in cell-cycle regulation and DNA repair, which was validated by quantitative RT-PCR and was associated with in vivo response to this HDACi. Increased phospho-H2AX levels, a marker of DNA damage, were measured in T-ALL cells from Givinostat responders. These results indicate that the induction of the DNA damage response could be an early biomarker of the therapeutic effects of Givinostat in T-ALL models. This information should be considered in the design of future clinical trials with HDACis in acute leukemia.
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pinazza
authors.affiliation: Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Borga
authors.affiliation: Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, Padova, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Agnusdei
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Minuzzo
authors.affiliation: Italfarmaco S.p.A, Milano, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Fossati
authors.affiliation: Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Paganin
authors.affiliation: Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Michielotto
authors.affiliation: Clinical Trials and Biostatistics Unit, Istituto Oncologico Veneto IRCCS, Padova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: De Paoli
authors.affiliation: Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Basso
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.|Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, Padova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Amadori
authors.affiliation: Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: te Kronnie
authors.affiliation: Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Indraccolo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002219:Carbamates / Q000008:administration & dosage*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D002219:Carbamates; D056572:Histone Deacetylase Inhibitors; C575255:givinostat