Abstract
Original language | English |
---|---|
Pages (from-to) | 80-90 |
Number of pages | 11 |
Journal | Haematologica |
Volume | 103 |
Issue number | 1 |
DOIs | |
Publication status | Published - 2018 |
Keywords
- ATM protein
- CD34 antigen
- checkpoint kinase 2
- daunorubicin
- sirtuin 6
- acute myeloid leukemia
- acute myeloid leukemia cell line
- Article
- blast cell
- cell disruption
- cell isolation
- cell proliferation
- clinical outcome
- deacetylation
- DNA damage
- DNA damage response
- DNA repair
- DNA replication
- enzyme activity
- flow cytometry
- gene expression
- gene knockdown
- gene overexpression
- genome
- genomic instability
- genotoxicity
- hematopoietic cell
- HL-60 cell line
- human
- immunofluorescence
- immunoprecipitation
- in vitro study
- in vivo study
- leukemia cell
- nonhuman
- pathogenesis
- peripheral blood mononuclear cell
- primary cell
- prognosis
- protein depletion
- protein phosphorylation
- receptor down regulation
- staining
- stem cell
- tumor cell
- tumor engraftment
- tumor growth
- U-937 cell line
- Western blotting
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Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents. / Cagnetta, A.; Soncini, D.; Orecchioni, S.; Talarico, G.; Minetto, P.; Guolo, F.; Retali, V.; Colombo, N.; Carminati, E.; Clavio, M.; Miglino, M.; Bergamaschi, M.; Nahimana, A.; Duchosal, M.; Todoerti, K.; Neri, A.; Passalacqua, M.; Bruzzone, S.; Nencioni, A.; Bertolini, F.; Gobbi, M.; Lemoli, R.M.; Cea, M.
In: Haematologica, Vol. 103, No. 1, 2018, p. 80-90.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells’ vulnerability to DNA-damaging agents
AU - Cagnetta, A.
AU - Soncini, D.
AU - Orecchioni, S.
AU - Talarico, G.
AU - Minetto, P.
AU - Guolo, F.
AU - Retali, V.
AU - Colombo, N.
AU - Carminati, E.
AU - Clavio, M.
AU - Miglino, M.
AU - Bergamaschi, M.
AU - Nahimana, A.
AU - Duchosal, M.
AU - Todoerti, K.
AU - Neri, A.
AU - Passalacqua, M.
AU - Bruzzone, S.
AU - Nencioni, A.
AU - Bertolini, F.
AU - Gobbi, M.
AU - Lemoli, R.M.
AU - Cea, M.
N1 - Cited By :5 Export Date: 5 February 2019 CODEN: HAEMA Correspondence Address: Cea, M.; Department of Internal Medicine (DiMI), University of GenovaItaly; email: michele.cea@unige.it Chemicals/CAS: checkpoint kinase 2, 244634-79-5; daunorubicin, 12707-28-7, 20830-81-3, 23541-50-6 Funding details: Associazione Italiana per la Ricerca sul Cancro, AIRC Funding details: Associazione Italiana per la Ricerca sul Cancro, AIRC, 18491 Funding text 1: This work was supported in part by the Associazione Italiana per la Ricerca sul Cancro (AIRC, My First Grant #18491, to MC), Italian Ministry of Health (5 x 1000 Funds of IRCCS San Martino-IST 2014, to MC), Associazione Italiana Leucemie & Società Italiana di Ematologia Sperimentale fellowship (AIL-SIES, to DS) and University of Genova, Italy. 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PY - 2018
Y1 - 2018
N2 - 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. © 2018 Ferrata Storti Foundation.
AB - 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. © 2018 Ferrata Storti Foundation.
KW - ATM protein
KW - CD34 antigen
KW - checkpoint kinase 2
KW - daunorubicin
KW - sirtuin 6
KW - acute myeloid leukemia
KW - acute myeloid leukemia cell line
KW - Article
KW - blast cell
KW - cell disruption
KW - cell isolation
KW - cell proliferation
KW - clinical outcome
KW - deacetylation
KW - DNA damage
KW - DNA damage response
KW - DNA repair
KW - DNA replication
KW - enzyme activity
KW - flow cytometry
KW - gene expression
KW - gene knockdown
KW - gene overexpression
KW - genome
KW - genomic instability
KW - genotoxicity
KW - hematopoietic cell
KW - HL-60 cell line
KW - human
KW - immunofluorescence
KW - immunoprecipitation
KW - in vitro study
KW - in vivo study
KW - leukemia cell
KW - nonhuman
KW - pathogenesis
KW - peripheral blood mononuclear cell
KW - primary cell
KW - prognosis
KW - protein depletion
KW - protein phosphorylation
KW - receptor down regulation
KW - staining
KW - stem cell
KW - tumor cell
KW - tumor engraftment
KW - tumor growth
KW - U-937 cell line
KW - Western blotting
U2 - 10.3324/haematol.2017.176248
DO - 10.3324/haematol.2017.176248
M3 - Article
VL - 103
SP - 80
EP - 90
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 1
ER -