An immediate transcriptional signature associated with response to the histone deacetylase inhibitor Givinostat in T acute lymphoblastic leukemia xenografts

M. Pinazza, C. Borga, Valentina Agnusdei, S. Minuzzo, G. Fossati, M. Paganin, B. Michielotto, Angela De Paoli, G. Basso, A. Amadori, G. Te Kronnie, S. Indraccolo

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere2047
JournalCell Death and Disease
Volume7
DOIs
Publication statusPublished - Jan 14 2016

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Histone Deacetylase Inhibitors
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Heterografts
DNA Damage
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Inbred NOD Mouse
SCID Mice
Gene Expression Profiling
Therapeutic Uses
Hematologic Neoplasms
Cytogenetics
DNA Repair
Cell Cycle
Leukemia
Biomarkers
givinostat
Clinical Trials
Pediatrics
Apoptosis
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

An immediate transcriptional signature associated with response to the histone deacetylase inhibitor Givinostat in T acute lymphoblastic leukemia xenografts. / Pinazza, M.; Borga, C.; Agnusdei, Valentina; Minuzzo, S.; Fossati, G.; Paganin, M.; Michielotto, B.; De Paoli, Angela; Basso, G.; Amadori, A.; Te Kronnie, G.; Indraccolo, S.

In: Cell Death and Disease, Vol. 7, e2047, 14.01.2016.

Research output: Contribution to journalArticle

Pinazza, M. ; Borga, C. ; Agnusdei, Valentina ; Minuzzo, S. ; Fossati, G. ; Paganin, M. ; Michielotto, B. ; De Paoli, Angela ; Basso, G. ; Amadori, A. ; Te Kronnie, G. ; Indraccolo, S. / An immediate transcriptional signature associated with response to the histone deacetylase inhibitor Givinostat in T acute lymphoblastic leukemia xenografts. In: Cell Death and Disease. 2016 ; Vol. 7.
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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.",
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