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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |