Cargando…

Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents

Genomic instability plays a pathological role in various malignancies, including acute myeloid leukemia (AML), and thus represents a potential therapeutic target. Recent studies demonstrate that SIRT6, a NAD(+)-dependent nuclear deacetylase, functions as genome-guardian by preserving DNA integrity i...

Descripción completa

Detalles Bibliográficos
Autores principales: Cagnetta, Antonia, Soncini, Debora, Orecchioni, Stefania, Talarico, Giovanna, Minetto, Paola, Guolo, Fabio, Retali, Veronica, Colombo, Nicoletta, Carminati, Enrico, Clavio, Marino, Miglino, Maurizio, Bergamaschi, Micaela, Nahimana, Aimable, Duchosal, Michel, Todoerti, Katia, Neri, Antonino, Passalacqua, Mario, Bruzzone, Santina, Nencioni, Alessio, Bertolini, Francesco, Gobbi, Marco, Lemoli, Roberto M., Cea, Michele
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ferrata Storti Foundation 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777193/
https://www.ncbi.nlm.nih.gov/pubmed/29025907
http://dx.doi.org/10.3324/haematol.2017.176248
_version_ 1783294174648336384
author Cagnetta, Antonia
Soncini, Debora
Orecchioni, Stefania
Talarico, Giovanna
Minetto, Paola
Guolo, Fabio
Retali, Veronica
Colombo, Nicoletta
Carminati, Enrico
Clavio, Marino
Miglino, Maurizio
Bergamaschi, Micaela
Nahimana, Aimable
Duchosal, Michel
Todoerti, Katia
Neri, Antonino
Passalacqua, Mario
Bruzzone, Santina
Nencioni, Alessio
Bertolini, Francesco
Gobbi, Marco
Lemoli, Roberto M.
Cea, Michele
author_facet Cagnetta, Antonia
Soncini, Debora
Orecchioni, Stefania
Talarico, Giovanna
Minetto, Paola
Guolo, Fabio
Retali, Veronica
Colombo, Nicoletta
Carminati, Enrico
Clavio, Marino
Miglino, Maurizio
Bergamaschi, Micaela
Nahimana, Aimable
Duchosal, Michel
Todoerti, Katia
Neri, Antonino
Passalacqua, Mario
Bruzzone, Santina
Nencioni, Alessio
Bertolini, Francesco
Gobbi, Marco
Lemoli, Roberto M.
Cea, Michele
author_sort Cagnetta, Antonia
collection PubMed
description Genomic instability plays a pathological role in various malignancies, including acute myeloid leukemia (AML), and thus represents a potential therapeutic target. Recent studies demonstrate that SIRT6, a NAD(+)-dependent nuclear deacetylase, functions as genome-guardian by preserving DNA integrity in different tumor cells. Here, we demonstrate that also CD34(+) blasts from AML patients show ongoing DNA damage and SIRT6 overexpression. Indeed, we identified a poor-prognostic subset of patients, with widespread instability, which relies on SIRT6 to compensate for DNA-replication stress. As a result, SIRT6 depletion compromises the ability of leukemia cells to repair DNA double-strand breaks that, in turn, increases their sensitivity to daunorubicin and Ara-C, both in vitro and in vivo. In contrast, low SIRT6 levels observed in normal CD34(+) hematopoietic progenitors explain their weaker sensitivity to genotoxic stress. Intriguingly, we have identified DNA-PKcs and CtIP deacetylation as crucial for SIRT6-mediated DNA repair. Together, our data suggest that inactivation of SIRT6 in leukemia cells leads to disruption of DNA-repair mechanisms, genomic instability and aggressive AML. This synthetic lethal approach, enhancing DNA damage while concomitantly blocking repair responses, provides the rationale for the clinical evaluation of SIRT6 modulators in the treatment of leukemia.
format Online
Article
Text
id pubmed-5777193
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Ferrata Storti Foundation
record_format MEDLINE/PubMed
spelling pubmed-57771932018-02-02 Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents Cagnetta, Antonia Soncini, Debora Orecchioni, Stefania Talarico, Giovanna Minetto, Paola Guolo, Fabio Retali, Veronica Colombo, Nicoletta Carminati, Enrico Clavio, Marino Miglino, Maurizio Bergamaschi, Micaela Nahimana, Aimable Duchosal, Michel Todoerti, Katia Neri, Antonino Passalacqua, Mario Bruzzone, Santina Nencioni, Alessio Bertolini, Francesco Gobbi, Marco Lemoli, Roberto M. Cea, Michele Haematologica Article Genomic instability plays a pathological role in various malignancies, including acute myeloid leukemia (AML), and thus represents a potential therapeutic target. Recent studies demonstrate that SIRT6, a NAD(+)-dependent nuclear deacetylase, functions as genome-guardian by preserving DNA integrity in different tumor cells. Here, we demonstrate that also CD34(+) blasts from AML patients show ongoing DNA damage and SIRT6 overexpression. Indeed, we identified a poor-prognostic subset of patients, with widespread instability, which relies on SIRT6 to compensate for DNA-replication stress. As a result, SIRT6 depletion compromises the ability of leukemia cells to repair DNA double-strand breaks that, in turn, increases their sensitivity to daunorubicin and Ara-C, both in vitro and in vivo. In contrast, low SIRT6 levels observed in normal CD34(+) hematopoietic progenitors explain their weaker sensitivity to genotoxic stress. Intriguingly, we have identified DNA-PKcs and CtIP deacetylation as crucial for SIRT6-mediated DNA repair. Together, our data suggest that inactivation of SIRT6 in leukemia cells leads to disruption of DNA-repair mechanisms, genomic instability and aggressive AML. This synthetic lethal approach, enhancing DNA damage while concomitantly blocking repair responses, provides the rationale for the clinical evaluation of SIRT6 modulators in the treatment of leukemia. Ferrata Storti Foundation 2018-01 /pmc/articles/PMC5777193/ /pubmed/29025907 http://dx.doi.org/10.3324/haematol.2017.176248 Text en Copyright© 2018 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.
spellingShingle Article
Cagnetta, Antonia
Soncini, Debora
Orecchioni, Stefania
Talarico, Giovanna
Minetto, Paola
Guolo, Fabio
Retali, Veronica
Colombo, Nicoletta
Carminati, Enrico
Clavio, Marino
Miglino, Maurizio
Bergamaschi, Micaela
Nahimana, Aimable
Duchosal, Michel
Todoerti, Katia
Neri, Antonino
Passalacqua, Mario
Bruzzone, Santina
Nencioni, Alessio
Bertolini, Francesco
Gobbi, Marco
Lemoli, Roberto M.
Cea, Michele
Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents
title Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents
title_full Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents
title_fullStr Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents
title_full_unstemmed Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents
title_short Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents
title_sort depletion of sirt6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to dna-damaging agents
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777193/
https://www.ncbi.nlm.nih.gov/pubmed/29025907
http://dx.doi.org/10.3324/haematol.2017.176248
work_keys_str_mv AT cagnettaantonia depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT soncinidebora depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT orecchionistefania depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT talaricogiovanna depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT minettopaola depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT guolofabio depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT retaliveronica depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT colombonicoletta depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT carminatienrico depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT claviomarino depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT miglinomaurizio depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT bergamaschimicaela depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT nahimanaaimable depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT duchosalmichel depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT todoertikatia depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT neriantonino depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT passalacquamario depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT bruzzonesantina depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT nencionialessio depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT bertolinifrancesco depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT gobbimarco depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT lemolirobertom depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents
AT ceamichele depletionofsirt6enzymaticactivityincreasesacutemyeloidleukemiacellsvulnerabilitytodnadamagingagents